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Home , Lung transplantation

Eur Respir J REVIEW 1990, 3 , 594-605

Transplantation of the

T. Higenbottam, B.A. Otulana, J. Wallwork

Transplantation of the lung. T . Higenbottam, BA. Otulana, J. Wallwork. Dept of Respiratory Physiology, Papworth Hospital, ABSTRACT: The Introduction of cyclosporlne as a highly effective Papwonh Everard, Cambridge CB3 8RE, UK. Immunosuppressive agent and the development of new techniques for heart­ lung and have led to a new treatment for a wide Correspondence: Dr T. Higenbottam, Dept of range of fatal cardiopulmonary diseases. Indications for are now Respiratory Physiology, Papwonh Hospital, Papwonh Everard, Cambridge CB3 8RE, UK. becoming clear, together with major contra-indications. Suppurative lung disease, such as , can be effectively treated by heart-lung Keywords: Lung transplantation, heart-lung transplan­ transplant (HLT). A whole new field or pulmonary medJcine is emerging tation, lung rejection, obliterative bronchiolitis. to provide the physiological monitoring and diagnostic techniques for major complications such as opportunistic lung Infection and pulmonary Received: August, 1989; accepted after revision rejection. Obllteratlve bronchiolitis, a consequence of frequent and severe November 30, 1989. rejection, stlU provides a major challenge to the immunological scientist and respiratory physician. Lung transplantation, by disrupting the vascu­ lar supply and innervation of the lung, Is raising major questions about the generally accepted beliefs of regulation of breathing and pulmonary mechanics. Finally, as the survival rate improves beyond the current SO% at 3 yrs, lung transplantation will perhaps present further challenges to our understanding of the pathogenesls of various diseases such as asthma and cystic fibrosis. Eur Respir 1., 1990, 3, 594-605.

Tbe surgical techniques long-tenn survival. The healing of the tracheal anasto­ mosis, with the "en bloc" technique, is aided by With the clinical success of renal and cardiac collateral blood supply arising from the mcdiatinum, transplantation tremendous interest developed in the principally the coronary arteries which supply the lower possibility of lung and heart-lung transplantation for and carina [9]. end-stage cardiopulmonary and lung disease. Early Widespread use of HLT is limited by availability of animal studies confirmed the technical feasibility of lung suitable donors, particularly as cardiac transplantation is transplantation, but concern remained about long-tenn so successful [10]. Single lung transplantation offers a survival, particularly in the absence of vagal innervation solution by enabling and heart to be used for of the lung [1]. Non-primate mammals appear unable to separate recipients. The introduction of the "omental sustain ventilation without pulmonary vagal innervation wrap" [11) mobilizing the omentum and wrapping it but, fortunately, primates [2] including man sustain around the bronchial anastomosis has contributed to nonnal ventilation despite loss of pulmonary vagal clinically successful single lung transplantation [12]. innervation [3]. Double lung transplantation, without the heart has also Early experience of clinical lung transplantation was been described [13] but tracheal anastomosis healing is not promising, long-tenn survivors being rare [4]. One poorer than in HLT presumably because of the loss of of the main problems encountered by early workers mediastinal collaterals. Alternatively bilateral bronchial involved the healing of the airway anastomosis [5]. Two anastomosis with "omental wraps" may offer a solution scientific developments, however, provided a solution. to enable double lung transplantation [14]. But as HLT In 1976, BoREL et al. discovered the powerful appears so successful, to enhance the availability of donor immunosuppressive, cyclosporine (previously called organs the "domino" operation has been devised where cyclosporin A) which inhibits T lymphocyte helper cells, the heart of the HLT recipient is donated to another probably by binding to a specific protein receptor, called cardiac recipient. cyclophilin [7]. High dose steroids could be avoided, particularly during the early post-operative period, by use of cyclosporine, with clear benefits to wound heal­ Medical after care ing. Using an earlier report of a similar surgical tech­ nique, REITZ et al. in Stanford [8] developed the "en Early experience of lung transplantation identified two bloc" heart-lung transplant (HL1) operation in a primate major problems in aftercare. The first was a high model in combination with cyclosporine to achieve incidence of primary failure, so called TRANSPLANTATION OF THE LUNG 595 post-implantation syndrome which closely resembles adult Table 1. - Causes of early surgical death in eight respiratory distress syndrome [15]. The second was the heart-lung transplant (HLT) recipients in the immediate inability to detect graft rejection and distinguish rejec­ post-operative period tion from pulmonary infection; lung rejection in a chronic Number of patients form contributing to long-term graft failure [16]. Cause of death Cerebrovascular event 2 Tracheal dehiscence 1 Preservation of the donor lung Inflated/ruptured aorta 1 Small bowel infarction/SLE 1 It is essential that after lung transplantation, the new ARDS/hepatic dysfunction 1 graft function immediately. There is no equivalent to Early graft failure 1 haemodialysis, which is used in renal transplantation to ensure the patient's survival until the graft begins to Total 7 out of 61 operations function. During the donor operation and with subse­ ARDS: adult respiratory distress syndrome. quent transportation to the recipient the lungs experience prolonged ischaemia. To reduce ischaemic injury solid organs are cooled [17]. Colloidal solutions seem beuer vehicles to cool the lungs than crystaloid solutions [18]. Table 2. - Criteria for donor selection Also, it is probably better to keep the lungs inflated than 1. Age below 40 yrs. deflated [19] in preserving function. Using these prin­ 2. No major thoracic trauma. ciples the early HL T surgery involved transporting the 3. No past history of pulmonary disease, including asthma. donor to the recipient hospital, the donor and recipient 4. A short period of ventilation. operations being performed in adjoining operating 5. No systemic or pulmonary infections. theatres to reduce to a minimum the ischaemic time. 6. Normal chest X-ray. Obvious practical and ethical problems ensued from 7. Normal lung compliance with peak inspiratory pressure moving donors, which limited availability, a method for <20 nunHg, tidal volume of <15 ml·kg·1 and respiratory 1 long-term preservation was therefore needed. rate 10-14 br·min· • 8. Normal gas exchange, arterial oxygen tension (Pao2) ) 300 • <15 kPa with fractional inspiratory oxygen (Fto2 30%. 9. Inotropic requirement <10 )J.g·kg"1·min·1 of dopamine or dobutamine. 10. Normal electrocardiogram (ECG). 250 vascular bed, before infusion of a single flush colloidal 200 based preservation solution [21, 22). This method • achieves ischaemic times up to 5.5 h and excellent <>I 0 :I: E immediate graft function (fig. 1}. Only one primary graft E failure occurred in 61 HLT patients where most were 150 • 8c extubated within 24 h of surgery (table 1). At present the ~ 0 main limit to the ischaemic time in HLT is probably the 0 '0= inability to preserve cardiac function. N 0 0 0... 100· 0 No matter how effective the long-term preservation c( system, careful selection of the donor organs is impor­ • tant (table 2) to lessen the risks of using injured or 50· damaged lungs and to avoid obviously infected organs.

0 Diagnosis of lung rejection After Pre- One week bypass extubation postoperatlvely Lung rejection was a major problem in the early ) Fig. I. - Alveolar·atterial oxygen gradient (A-ao2 for near and distant experience of transplantation. Repeated untreated acute procurement groups at various times post-operatively. rejection is now thought to have contributed to the dis­ abling and fatal airways obstruction seen in up to 50% Recently a number of methods have been described to of HLT patients [20, 23). With HLT it had been thought extend ischaemic times to enable procurement of organs that endomyocardial (EMB), a method established from distant hospitals. One such method involves a to diagnose rejection in cardiac transplantation [24], could mechanical system which perfuses the heat-lung block be used to monitor rejection. However, both experimen­ during transportation [20]. Another was using tal [25] and clinical [26) studies suggest that the lungs to cool the lungs before har­ undergo rejection before the heart. Indeed we have now vesting. Perhaps the simplest method uses intravenous abandoned the use of EMB in HLT patients as cardiac prostacyclin (PGI2) to vasodilate the donor's pulmonary rejection is rare if the lung rejection is controlled [27]. 596 T. HIGENBOTTAM, B.A. OTID..ANA, J. WALLWORK Additionally, HLT patients commonly experience pul­ A monary infections [20]; the same is true for single lung transplant patients [12]. Transbronchial lung biopsy (TBB) through a 140 FEV1 fibreoptic bronchoscope provides a sensitive means for diagnosing lung rejection [28] anq enables distinction 120 from pulmonary infection [29]. The technique has now "0 been extended to child HLT patients [30]. G) With a clear hiStological diagnosis it has proved pos­ ..Q. 100 sibte to demonstrate the clinical featw:~ of rejection and -1. mfection. For example, the che5t radiograph is commonly 0 80 nonnal during acute rejection episodes (ta.ble 3) [31] but >""' spirometric volumes and total lu11g capacity fall (table 4 Ul and fig. 2) [32]. Indeed, pntients can monitor lung func­ u. 60 tion daily using a battery operated pocket spirometer, providing and early indication for TBB [33]. The use of a simple preservation system, close moni­ 40 toring of pulmonary function and TBB have been associated with improved survival figures [34]. 20 B D D A Table 3. - Prevalence of abnormal chest radiograph in histologically diagnosed acute heart-lung transplant patients Rejec.tion Within 1 morith After 1 month 8 of surgery of surgery Normal CXR 6 17 Abnormal CXR 17 5 140 Total 23 22 120 DLCO Radiographs taken in the first month post-transplant are "0 compared with those taken thereafter. CXR: chest X-ray. ~Q. 100

Table 4. - Mean values of lung function measurements 0-J. before, during and after acute lung rejection 0 80 0 FEV1 VC TLC TLco .J I I l mmol·kPa·1·min·1 0 60 First 3 months (n=l4) 40

Before 2.5 2.8 4.7 6.0 During 1.7 1.9 3.8 4.3 20 After 2.2 2.3 4.6 5.4 8 D D A

LSD 0.3 0.4 0.5 0.8 Fig. 2.- Changes in FEV1 and 1\.co on development of histologically· proven lung rejection and following treatment. Values are expressed as Subsequent months percentage predicted based on recipients' sex, age and height B: before; (n=16) : D: during; A: after, lung rejection; FEV1 forced expiratory volume in one second; 1\.co: transfer factor of the lungs for carbon monoxide. Before 2.8 3.4 5.9 6.0 During 2.3 3.1 5.6 5.7 After 3.0 3.7 5.8 6.1 Indications for lung and heart-lung transplantation LSD 0.3 0.3 0.4 0.3

Changes in lung function with 30 episodes of histologically Heart-lung transplantation diagnosed lung rejection and after trcaunent with augmented in heart-lung transplant (HLT) patients. Combined HLT was first introduced as a treatment for Rejection is generally more severe in the fl.I"St three montlt.s end-stage pulmonary vascular disease, Eisenmenger's post-transplant. FEY~ forced expiratory volume in one second; VC: vital capacity; TLC: total lung capacity; Tt.eo: transfer syndrome and primary [35]. It factor of the lung for carbon monoxide; LSD: least significant has since been extended to chronic lung disease [36] difference comparing pairs of means at p=0.05. including cystic fibrosis [37]. TRANSPLANTATION OF THE LUNG 597

Eisenmenger' s syndrome Cystic fibrosis (CF) is the most common fatal inherited disease in Caucasians [47]. Since the location Secondary pulmonary hypertension developing as a of the CF gene upon human chromosome 7cen-q22 result of congenital cardiac right to left shunts, [48-50] the quest is to provide a pre-natal diagnosis but commonly ventricular septal defects or patent ductus until then medical care is directed to limiting the conse­ arteriosus, causes considerable restriction of life style and quences of the disease. Despite many advances patients is ultimately fatal. The development of right ventricular die in early adulthood, usually from decompensation with fluid retention is a poor prognostic from chronic suppurative lung disease, the cause of which sign, but it is difficult to predict the survival chances of remains unknown but is putatively linked to abnormal an individual patient. For this reason patient selection chloride ion transport across the epithelium [51]. Heart­ remains imprecise. lung transplantation now offers a chance of survival to such patients [37]. Furthermore, after lung transplanta­ tion, the donor lung retains normal ionic transport across Primary pulmonary hypertension (PPH) the respiratory epithelium [52). In other words, epithelial abnormality does not recur within the transplanted lung. This is a rare condition afflicting young adults, although children and older patients can develop the Table 5. - Diseases treated by lung and heart-lung disease [38). Women are more often affected than men. transplantation Without a clear idea of the mechanism by which the Lung Heart-lung disease develops the division of the condition according transplantation transplantation to the predominant histopathological abnormality is not helpful in deciding on prognosis. Three predominate Cystic fibrosis Double lung in future Good results types are seen [39], namely plexogenic pulmonary Fibrosing alveolitis Single lung good results Good results arteriopathy, peripheral thrombotic and vena-occlusive Eosinophilic No reports Good results disease. Commonly the first two forms occur together granuloma in the same patient [40). Sarcoid No reports Good results The natural history of the disease is however No reports Qood results becoming clear. From a retrospective study of 120 patients at the Mayo Clinic [41] patients with a mixed Table 6.- Indications for lung transplantation and heart­ venous oxygen saturation (SVo ), measured from a pul­ 2 lung transplantation monary arterial blood sample, of <63% have only a 17% chance of surviving 3 yrs. Up to 55% of patients with Chronic lung disease Svoz>63% may survive three yrs. The Svo2 % reflects the low .cardiac index in PPH patients, which is a result 1. FEY1 <25% of the marked obstruction and obliteration of the small 2. TLCO <50% pulmonary arteries causing the rise in pulmonary vas­ 3. Hypoxic respiratory failure with or without hypercapnia cular resistance. 4. Evidence of cor pulmonale After diagnostic right heart catheterization patients for a) Right axis deviation on ECG b) Raised mean pulmonary artery pressure on Doppler HLT cail be selected according to the Svo2 % or cardiac output. However, as prolonged delays are likely until a echocardiogram suitable donor can be found, many patients can be c) Fluid retention despite diuretics expected to die before HLT is possible. Vasodilator : FEY1 forced expiratory volume in one second; TLCO: transfer treatment may be effective in improving patients haemo­ factor of the lungs for carbon monoxide; ECG: electrocardio­ dynamics and lessening symptoms [42-44] although gram survival may not be affected [45]. Continuous long-term infusion of prostacyclin (PGiz) by a subclavian line has been used successfully to "by time" before transplant­ Contra-indications to heart-lung transplantation ation in severely afflicted patients [44). A patient for HLT must have a stable social back­ ground and a positive attitude towards life. Previous Chronic lung disease thoracic and cardiovascular surgery are no longer absolute contraindications, this includes pulmonary Following the success of HLT for pulmonary vascular lobectomy or previous corrective cardiac surgery. disease,. its use was extended to treat chronic lung However, pleurectomy and for recurrent disease [36]. A wide range of diseases have been treated pneumothorax remains a contraindication because of successfully (table 5) including emphysema, lung enhanced risks of chest wall bleeding after surgery. fibrosis and bronchiectasis. Patients are selected accord­ Localized pulmonary infection, which will be removed ing to degree of respiratory failure, severity of ventila­ at surgery, is not a contraindication. But pulmonary tory dysfunction and evidence of cor pulmonale (table aspergillus fwnigatus infections, particularly mycetoma, 6), the latter feature providing a powerful guide to prog­ are excluded due to fears that pleural disease will not nosis [46]. be eradicated by surgery. 598 T. HIGENBOTTAM, B.A. OTULANA, J. WALLWORK

Multi-organ disease is becoming less of a problem, fall initially after surgery. This fall is comparable with e.g. severe can be treated by simultaneous the change in function after median sternotomy for coro­ liver and heart-lung transplantation [53]. Insulin depend­ nary artery surgery [54] and probably reflects a change ent diabetes mellitus is no longer a contraindication. in configuration of the chest wall and rebs [55]. However, transplantation of critically sick patients on Subsequently the 'ILC returns to pre-operative values life support systems remains an absolute contraindica­ (fig. 3). The final value appears uninfluenced by the donor tion because survival results are so poor in such patients. lung size and seems to be determined by the recipients's It represents, therefore, an inappropriate use of resources. chest wall size [56].

160 Lung Transplantation

The shortage o~ suitable donors for HLT together with the competing needs for cardiac transplantations have 140 led to alternative approaches to lung transplantation of , which single and double lung transplants are most 0 t. recently described. a. 120 t 0 Single lung transplantation J 1- 100 This was first introduced, after the introduction of ..r:: cyclosporine, for the treatment of cryptogenic fibrosing .! alveolitis [12], with good long-term results. The patients a. so treated were in respiratory failure with severe venti­ u 80 Iatory and gas diffusion abnormalities. G) Early experience of single lung transplantation, before a: the cyclosporine era, suggested that single lung trans­ plantation could not be used in emphysema or primary 60 pulmonary hypertension, due to the post-operative imbalance of distribution of ventilation and perfusion. However, improved surgical techniques and better organ preservation now make single lung transplantation suit­ 40 able for emphysema and pulmonary hypertension (A. Pre-HLT 2 6 12 Pauerson, personal communication). Time posi·HLT months Fig. 3. - The change in individual values for total lung capacity (J'LC) Double lung transplantation in 14 heart-lung 11ansplant (HLT) patients foUowed up for 12 monlhs after transplantation. In most cases, the TLC returned to the Introduced to enable the use of the donor heart for pro-transplant level at 1 yr, after the initial fall at 1 month. another recipient, double lung transplantation is still at an innovative stage, perhaps reflecting the concern about The effect of recipient's thoracic dimensions on trans­ the healing of tracheal anastomosis. As a new develop­ planted lung size ment bilateral bronchial anstomosis and double lung transplantation has been attempted, long-term results are Most methods for matching the donor lung size to the awaited. recipient's thoracic cavity volumes depend upon meas­ The main area where double lung transplantation may urements from radiographs [21, 22]. These methods be of value is in CF [13]. Suppuralive lung disease simply offer an assessment of height [56]. As recipients precludes single lung transplantation due to fears that the have a wide range of lung disease, causing their thoracic infection of the remaining lung will spill over into the cavities to be larger than predicted, e.g. as in emphy­ new transplanted lung. sema, or smaller as in cryptogenic fibrosing alveolitis, matching donor and recipient height leads to patients receiving donor lungs up to 4 1 too small or up to 2 l too Long-term function of the lungs after large (fig. 4) [56]. Despite these disparities in size, the transplantation final TI..C of the recipient is close to their pre-operative value (fig. 3), suggesting that the chest wall in adults The pulmonary function improves after single lung provides the major volumetric constraint for lung vol­ [12], double lung [13] and heart-lung transplantation ume. From these considerations a simple guideline to [36, 37] for chronic lung disease. In HLT the total lung matching donor and recipients ling size is to use the capacity (TLC) and spirometric values, forced expiratory recipients's 'ILC measured before surgery and the donor's ) volume in one second (FEV1 and vital capacity (VC), predicted 1LC obtained from height, age and sex [56]. TRANSPLANTATION OF TilE LUNG 599

2 HI s I] r.:J 1 ••••••••••••••••••••••••••••• •••••••••••••••••••• Ji:l ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• + 1SD (/) f mm r.:J m ~ 0 r.:J l:ll:i::J r.:J 0 ------G--~~------M~n ...J a 1- ·1 a m Efl m r.:J s ·-c 1:] B ...... l!ii!J''''''''''···I!I················· -1so c ·2 ,....C1) C1) c:5-3

-4

-5 2 4 6 8 10 Recipient pre-HLT TLC litres

Fig. 4.- A plot of the difference in total lung capacily (TLC) between donor and recipients of heart-lung transplant (HL1) against the recipients' measured TLC. There is a trend towards less difference at larger volwne of recipients' lung.

Indices of airflow in the transplanted lung Gas diffusion in lung transplantation

It has been noted in several studies that early after sur­ In lung transplantation, single lung [12], double lung gery, HLT patients have low values for airways [13] and heart-lung [56] transplantation the TLco tends resistance [57, 58] and forced expiratory flow volume to be lower than normal. In part this reflects the anaemia curve analysis reveals that expiratory flow instead of in the immunosuppressed patient but a complete expla­ declining linearly with volume, shows a plateau followed nation is not yet available [32] . by a "knee" and then a decline. As yet there is no expla­ nation for this observation, although it is similar to that Control of ventilation after seen in studies of dog lung and excised human lungs and lung transplantation this has been attributed to increased longitudinal tracheal tension [59]. Perhaps the tracheal anastomosis renders Pulmonary proprioceptive vagal afferent nerves, the trachea more rigid. Denervation seems an unlikely probably from slowly adapting stretch receptors, are explanation, as there is little evidence of re-innervation responsible for the Hering-Breuer inflation reflex [1]. In (see below) but airflow obstruction can develop [58]. anaesthetized animals this reflex contributes to the regulation of the breathing pattern [1] . This contribution causes termination of inspiration and prolongation of Lung rejection on lung function expiration. In man there is doubt as to the existence of the Hering­ With acute lung rejection, diagnosed by histology of Breuer inflation reflex at rest [61, 62]. Although it has TBB, it has been shown that TLC, FEV and VC been argued that such afferent information may be 1 decline. This is also true with pulmonary infection. Use important at higher levels of ventilation, early work can be made of to monitor graft function to depended upon relatively nonspecific reversible neural provide an early indication for TBB. Changes in single­ blockade. breath transfer factor for carbon monoxide (TLCo) are There is evidence that, at least up to 36 months after more variable in acute rejection. surgery, there is no afferent re-innervation of the lungs These volumetric changes with acute rejection and with HLT [63). Immunohistochemical studies of lung infection [32] are different from chronic lung rejection, tissue from HLT patients at death or re-transplantation so called oblitcrative bronchiolitis (OB) [58, 60], where revealed no afferent re-innervation (J. Polak, personal airflow obstruction dominates the pathophysiological communication). This is in parallel with in vivo picture. Here the flow-volume curve becomes re-implantation studies, where only very limited evidence curvilinear, FEV1 falling by a greater degree than VC. of afferent re-innervation can be found [64]. 600 T. HIGENBOTTAM, B.A. OTULANA, J. WALLWORK

Sao Paco (H) 2 2 5 100 ftl 6.0 0/.. c.. • • 98 ~ 5.5 45 .... 96 5.0 ._ ------. 40 7 4.5 ~ 94 2?55; E 35 92 4 .0 ~ 90 3.5 3 R E R E R E svo (H) 9 2 8 Pvco2 o/o c..ftl 80 ~ 7 70 .... ~ ":- 60 ~ 50 E 40 ~ 4 30 3 A E R E R

); ), Fig. 5. - Changes in arterial and mixed venous oxygen saturation (Sao,, Svo1 C01 tension (Paco,, FVco1 and hydrogen ion concentration (H) in 6 HLT patients from rest (R) to exercise (E) ef 50 W supine cycling. More striking changes occurred in the mixed venous than in the arterial blood in association with the exercise hyperventilation. HLT: heart·lung tansplant.

Studies of breathing pattern at rest in HLT patients re-implantation of canine single lungs show signs of show the same variation of tidal volume (VT) and breath­ efferent lung function but no convincing evidence that ing frequency (f) as nonnals both asleep and awake [65]. afferent nerves re-innervate the lungs [64]. In man, after Also, augmented breaths, "sighs" occurred at the same HLT, the cough response to ultrasonically nebulized frequency as nonnals. During hyperventilation, which distilled water (USNDW) is absent up to 36 months after occurs with carbon dioxide rebreathing, HL T patients surgery (fig. 6) [63]. The cough response to USNDW is show the same pattern of change in VT and duration of probably a result of stimulation of airway rapidly adapt­ inspiration (TI) as nonnals [66]. ing stretch receptors [71, 72). This can, therefore, be With exercise HLT patients, like heart transplant (HT) taken as evidence that at least there is no afferent patients, appear to hyperventilate [67, 68), i.e. the level re-innervation after HLT. of ventilation (YE) is excessive compared with oxygen uptake. This does not appear, therefore, to simply reflect denervation of the lungs because both HT and HLT 8 patients have similar responses, although the HT patients .,.. c retain pulmonary innervation. Instead, it appears related 'c to the delayed and poorer cardiac output response seen ·e both in HLT and HT patients with exercise compared to >-2 u nonnals [67, 68] which probably reflects cardiac dener­ c vation. As a result despite nonnal arterial gas tensions ::sQ) er and pH, with the exception of arterial carbon dioxide e tension lower (Paco ), the mixed venous blood shows a 2 .c.- 10 marked fall in Pvo and pH and rise in Pvco [69) 01 2 2 ::s cc (fig. 5). This disparity between nonnal arterial gases and 8 markedly altered mixed venous blood gases provides c support for the possible existence of chemoreceptors in c the central veins and right atria [70]. 0 aJCIJCIJCJ:Dt:DC Control of airway function after Heart-lung Controls HLT and lung transplantation transplants

Fig. 6. - Cough frequency during one minute inhalation of ultrasoni­ Lung transplantation and heart-lung transplantation cally nebulized distilled water in IS hean·lung transplant (IlLT) patients acutely disrupts neural and vascular elements of the lung. compared with 15 matched controls. There was a significant reduction Reinnervation of the lungs may occur. Experimentally, in cough response in the HLT patients. TRANSPLANTATION OF THE LUNG 601

In HLT the bronchial arterial supply to the lung is epithelial cells [83]. However, this may not be specific to interrupted. The tracheal anastomosis is probably per­ transplanted organs. fused by the collateral blood supply from the , Alternatively, it has been argued that OB is the end in particular the coronary artery supply [9). Evidence is result of vascular arteriosclerosis (84]. Certainly, coro­ now emerging that after transplantation the intrapulmon­ nary arterial vascular sclerosis is observed at autopsy in ary bronchi are perfused by retrograde flow along the HLT patients dying from OB and similar changes are bronchial arteries, pulmonary to bronchial arteries being seen in pulmonary arteries. In this context it is important responsible (73]. to remember that the obliterative bronchiolitis in HLT is Following HLT and lung transplantation, many patients a disease of the intrapulmonary airways, that is those show bronchial hyperresponsiveness to methacholine as parts of the graft dependent on retrograde blood flow in asthma, [74, 75]. This responsiveness is not associated from the pulmonary arteries [73]. The bronchi and bron­ with acute rejection [76]. It may reflect denervation chioles could be considered at risk from ischaemia if the hypersensitivity of airway smooth muscle muscarinic pulmonary blood flow were to be impeded as in acute receptors. In contract to methacholine responsiveness, rejection [29). Typically the major airways become HTL patients respond with bronchoconstriction to bronchiectatic whilst the small airways become fibrosed USNDW only in the presence of rejection [76). Bron­ (fig. 7). chial responsiveness in HLT illustrates separate mecha­ Whatever the mechanism, the close association between nisms of pharmacological challenge and physical frequency and severity of acute lung rejection and the challenge. It is possible that airway responses to distilled later development of OB enables recognition of patients water may depend upon a pathophysiological bronchial at risk at an early stage, when augmented immunosup­ artery response (76]. pressive treatment may prevent the disease [80].

The present chaJlenges presented by lung transplantation

The two greatest challenges facing lung transplanta­ tion are the development of airways disease, obliterative bronchiolitis aud pulmonary infection [20]. These two complications currently limit long-term survival.

Obliterative bronchiolitis in HLT

Unlike cardiac rejection in heart transplants, HLT patients do not experience acute life-threatening lung rejection [77]. However, 3~50% develop severe obstruc­ tive airways disease, an obliterative bronchiolitis (OB), which insidiously leads to morbidity and fatalities [20, 23]. Early clinical studies failed to demonstrate any correlation between the frequency of acute rejection and development of OB [78]. However, TBB by providing a more accurate means of diagnosing rejection and distin­ Fig. 7. - A photograph of a transplanted lung at post-mortem 3 yrs guishing it from pulmonary infections [29] has enabled after heart-lung transplantation. The cut swface shows fibrous oblitera· a correlation to be found. Those patients who develop tion of the airways. OB experience more frequent acute lung rejection and more severe rejection than those patients who remain Table 7. - Immunosuppressive regime for heart-lung well [79, 80]. The pattern is of frequent and severe acute transplant patients lung rejection occurring within a few months of surgery. This association between acute rejection and OB is similar Peri.operative Maintenance to experimental studies [81] and emphasizes the immu­ nological basis for the airways disease. Cyclosporine (4-6 mg·kg-1) Cyclosporine (6-10 mg·kg-1 Single lung transplantation is associated with OB (A. per day Pauerson and J. Dark, personal communication) but as yet its incidence is unknown and little investigation has Methy !prednisolone adjusted to been undertaken in these patients. 1 g + 125 mg for 3 days) keep WBC <6000·mm3 Much attention has been focused on the possibility Murine ATG x 3 days thl:}t OB was the result of an immunological process directed against airway epithelial cells [82). Indeed, HLT Azathioprine 3 mg·kg·1 per day patients show enhanced expression of certain class 11 major histocompatability (MHC) on airway WBC: white cell count. 602 T. HIGENBOTTAM, B.A. OTULANA, J. WALLWORK

Patients are managed on cyclosporine and aza~hioprine and trimethoprim for active PCP [90]. But it is important (table 7). With acute rejection, immunosuppression to note that many interfere with cyclosporine is augmented with three days of methylprednisolone, [90]. 0.5-1.0 g per day, followed by oral prednisolone, I Invasive Aspergillus fumigatus infections of the lung mg·kg·1 per day, decreasing to around 10 mg per day should still be treated with intravenous amphotericin. A over a 10 day period. Repeated TBB are then performed. total accummulative dose of 2 g should be achieved with 1 If they have not cleared then a further "pulse" of aug­ daily doses of 0.75 mg·kg· • The major concern is the mented immunosuppression is given. This approach may added nephrotoxicity of amphotericin and cyclosporine. have contributed to the reduced incidence of OB in our It has been argued that pulmonary infections cause series [80]. OB, particularly CMV pneumonia [20]. However, OB There is still much to be learned about the mechanisms patients have no more frequent infection of the lung than of OB but careful monitoring of lung function and active patients who have normal lungs [80]. An immunological management of acute lung rejection diagnosed by TBB mechanism for OB seems more likely. can influence outcome. The future of lung and heart-lung Pulmonary infection in lung transplant patients transplantation Much has been learnt about this new field of trans­ Pulmonary infections are common in lung transplant plantation over the last eight years. The surgical patients [85]. Diagnosis proved difficult until the intro­ techniques are well established but further prolongation duction of TBB, the clinical signs and symptoms of lung of the organ preservation time is needed to increase availa­ rejection and infection being similar [86]. bility of organs. Much depends however on the Bacterial, viral and fungal infections can be diagnosed establishment of a European-wide organization for donor by culture of TBB or specimens. organs. But even with such developments, lung trans­ Standard cytology can be used to diagnose cytomega­ plantation will remain a limited activity. lovirus (CMV) and Pneumocystis carinii (PC) pneumo­ The major obstacle to success is the problem of nias. Precision and sensitivity can now be increased by obliterative bronchiolitis. However, because of accessi­ using monoclonal antibody techniques, immunocyto­ bility of the lung to biopsy and to obtaining immunologi­ chemistry particularly for the early of CMV and cally active cells by means of bronchoalveolar lavage, it for PC. is likely that new insights into the mechanisms of acute Histological examination of TBBs is essential to rejection will be identified. exclude acute lung rejection. It is important to appreciate Perhaps we are now able to consider heart-lung and that both infection and rejection can co-exist in the lungs lung transplantation in the same light as cardiac trans­ of the same patients, up to 25% in one study [87]. In plantation, having moved from experimental to clinical addition, characteristic "owls eye" intracellular inclusions treatment. of CMV can be observed in TBB from patients with CMV pneumonia and these are associated with an alveolitic appearance [88]. Herpes simplex (HSV) References pneumonia also shows a characteristic intra-cellular 1. Coleridge HM, Coleridge JCG. - Reflexes evoked from inclusion on TBB [89]. In PC pneumonia, a foamy intra­ tracheobronchial tree and lungs. In; Handbook of Physiology. alveolar infiltrate is seen, the trophozoite being seen with The , Control of Breathing. Section 3, 11. a silver stain method. 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Webb WR, Howard HS. - Cardiopulmonary immunpsuppressive treatment is augmented can reduce transplantation. Surg Forum, 1957, 8, 313--317. frequency of HSV pneumonia [89]. This may also be 5. Montefusco CM, Veith FJ. - Lung transplantation. Surg true for CMV. CMV pneumonia is, however success­ Clin North Am, 1986, 66, 503-515. fully treated with gancyclovir [86, 88] together with 6. Borel JF, Feurer C, Magnee C, Stahelin H. - Effects of hyper-immune globulin if it is a primary infection. HSV the new anti-lymphocyte peptide cyclosporin A in animals. pneumonia can be effectively treated with intro-venous Immunology. 1977, 32, 1017-1025. acyclovir [89]. 7. Handschumacher RE, Harding MW, Rice J, Drugge RJ, Speicher DW.- Cyclophilin: a specific cytosolic binding protein A prophylactic co-trimoxazole at times of augmented for cyclosporin A. Science, 1984, 226, 544-547. immunosuppression can reduce the incidence of PCP. 8. Reitz BA. 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