Transplantation of the lungs

Respiratory Medicine (1989) 83, 459--466

Transplantation of the lungs R. L. SMYTH, T. W. HIGENBOTTAM*,J. P. SCOTT AND J. WALLWORK

Heart-Lung Transplant Research Unit, Papworth Hospital, Papworth Everard, Cambridge CB8 8RE, U.K.

Over the last eight years a completely new form of treatment has been introduced for end-stage pulmonary vascular disease and chronic lung disease, including cystic fibrosis. Lung transplantation and heart-lung transplantation have moved from an experimental and innovative stage to clinical treatments. The exclusion criteria for selecting potential recipients have become relaxed whilst preservation techniques have improved to allow ischaemic times of donor organs to be extended beyond 4 h. Monitoring of graft function with daily spirometry and use of transbronchial lung biopsy have enabled early diagnosis of lung rejection or infection and thus effective treatment. Lung transplantation and heart-lung transplantation, by their success, are providing new insight into lung disease and pulmonary physiology. Introduction

Heart-lung transplantation (HLT) was first performed in dogs by Demikov in the 1940s (1). However, long term survival of dogs is not possible (2) because pulmonary denervation abolishes the pulmonary propioreceptor information required to sustain ventilation (3). Primates can maintain ventilation without pulmonary afferent nerves (4) thus permitting longterm survivors in baboons and man. Two developments in the late 1970s made clinical HLT possible. First the drug cyclosporine, which acts by bl6cking the production ofinterleukin 2 and inhibiting the function of the T-helper lymphocyte (5), was used successfully in human transplantation in 1977 by Calne et at. (6). It proved to be a powerful immunosuppressive agent which reduced the requirements for steroid therapy, particularly during the early post-operative period. Secondly, Reitz et al. (7), developed in primates the 'en bloc' heart-lung transplant operation which achieved better tracheal anastomotic healing, apparently through preservation of mediastinal collateral blood supply from the coronary arteries to the lower trachea and carina. With these developments, the first successful long-term human heart-lung transpant operation was performed by Reitz and associates in Stanford in 198 i in a case of primary pulmonary hypertension (8). Unilateral human lung transplantation had been performed as early as 1963 (9), but early results were disappointing, healing of the bronchial anastomosis proving to be a major problem. Wrapping the bronchial anastomosis with an omental pedicle was shown

to restore systemic circulation to the donor bronchus and to protect against dehiscence (10). This manoeuvre, together with substitution ofcyclosporine for high dose corticosteroids improved postoperative bronchial healing (11) and successful unilateral lung transplantation was reported in 1986 (12). An obvious advantage of this procedure is the maximization of the availability of donor organs, as both donor lungs can be used for separate recipients and the heart for a cardiac transplant. The technique has been extended with the development of double lung transplantation (13). Although early reports of this procedure are encouraging, concern remains about anastomotic healing. With the development of the 'domino' operation during HLT where the heart of the recipient can be used as a donor heart, there would appear to be no added advantage to the double lung procedure Recipient Selection for Heart-Lung Transplantation

Early reports of heart-lung transplantation identified recipient selection as crucial for long term survival (14). H LT is now successful as a treatment for pulmonary vascular disease (8) and chronic lung disease (15), in particular cystic fibrosis (16). As experience has increased and survival improved, recipient selection has expanded to include children (17). Selection of patients (Table 1) is guided both by relevant prognostic indicators and degree of disability. Pulmonary Vascular Disease

Primary pulmonary hypertension is a rare condition with an appalling prognosis, despite a few exceptions *Correspondenceto: Dr T. W. Higenbottam,RespiratoryPhysiology whd'e remissions have been reported (18). It affects Department,PapworthHospital,Cambridge,U.K. predominantly young adults although both children 0954-611 t/89/060459+ 08 $03.00/0

© 1989BaillirreTindall

460

Problems in Practice

Table 1 Selection criteria for patients assessed for heartlung transplantation Primary pulmonary hypertension:

Mixed venous oxygensaturation Cardiac index

< 63% < 1.51min -I m -2

Eisenmenger "ssyndrome:

Evidence of fight ventricular failure Arterial oxygendesaturation on exercise Cystic Fibrosis:

Forced expiratory volume in one second < 30% predicted Hypoxic hypercapnic respiratory failure Evidence ofeor pulmonale

and older patients can be afflicted (19). Fuster et al. (20) in a study of 120 patients at the Mayo Clinic have identified the mixed venous oxygen saturation (S~o2%), measured in a sample of pulmonary arterial blood, as an important predictor of long term survival. In their series, patients with an S~o2 of less than 63% were shown to have a survival to 3 years of only 17%, compared with 55% for those with an SVo2of this level or above. A cardiac index of less than 1.51 min -t m -2 also suggests advanced disease and poor prognosis. Vasodilator therapy has been used for symptomatic relief in this condition by increasing cardiac output (21). We have shown that continuous long term intravenous infusion of prostacyclin (PGI2) by subclavian line increases exercise tolerance and may buy time in severely diseased patients who are awaiting HLT (22). Although this treatment does not affect the disease process, it has been shown to increase survival by as much as two fold in the first year (23). In Eisenmenger's syndrome, whether due to ventricular septal defect, atrial septal defect or patent ductus arterious survival is difficult to predict. The rate of symptomatic deterioration in this group is slower and may occur in a stepwise fashion but there is always an unpredictable risk of sudden death, massive haemoptysis, paradoxical embolism or cerebral abscess. Right ventricular failure which is unresponsive to diuretic therapy is a useful prognostic sign. We are currently evaluating the use of the twelve-minute walk (24) as an indicator of degree of disability and poor prognosis in this and other patient groups. A 12 min walking distance of less than 500 m with an oxygen saturation which falls below 60% during this exercise, suggests severe cardiorespiratory impairment.

Chronic Lung Disease A wide variety of chronic lung diseases have been treated successfully by HLT and lung transplantation

(15). These have included emphysema, pulmonary fibrosis, bronchiectasis, sarcoidosis, alpha-l-antitrypsin deficiency and histiocytosis X, but one of the most exciting developments has been the extension of this procedure to treat patients with cystic fibrosis. These patients were not initially considered suitable because of concerns of overwhelming sepsis in the immunocompromised patient and the possible recurrence of the inherited defect in the transplanted organs. However, they have been shown to survive HLT with excellent pulmonary function (16). The mucosal potential difference which is elevated in CF has been shown, to be normal below the tracheal anastomosis, whereas the upper trachea retains the high cystic fibrosis potential (25). Thus, over a period of one to 36 months after transplantation the epithelial abnormality does not recur in HLT CF patients. A forced expiratory volume in l s (FEV 0 below 30% predicted suggests severe airways obstruction and advanced disease (26). The development of hypoxic, hypocapnic respiratory failure and cor pulmonale have also been identified as poor prognostic indicators (27).

Recipient Selection for Single Lung Transplantation Single lung transplantation (LT) was initially introduced as a treatment for institial lung disease, including cryptogenic fibrosing alveolitis (12). Patients with emphysema or primary pulmonary hypertension were not considered suitable because of postoperative ventilation perfusion imbalance. However, it has very recently been suggested that with improvements in surgical techniques, the procedure may be feasible for these indications. Currently sepsis in the recipient is an absolute contraindication to single lung transplantation, double lung transplantation may prove successful in these cases.

Exclusion Criteria As experience of these procedures has increased, the exclusion criteria for HLT and LT have been considerably narrowed. The early experience of HLT showed that recipients who had had previous thoracic surgery were at very high risk of postoperative haemorrhage and death following transplantation (28). Although this was originally a contraindication in the Papworth series, it is no longer so and patients with previous sternotomy and thoracotomy have successfully received HLT. Previous pleurectomy or pleurodesis continue to be exclusion criteria (29). The presence of liver disease may cause postoperative complications from bleeding (16) and such patients are currently

Problems in Practice

excluded for HLT alone but they may be suitable candidates for a combined heart-lung and liver transplantation (30). Features previously considered to be contraindications include insulin dependent diabetes mellitus, steroid therapy and growth of Aspergillus fumigatus from the sputum. Many patients with these features have successfully received HLT, but the presence of an aspergilloma involving the pleura or chest wall is still an exclusion criterion. Table 2 Donor criteria

1. 2. 3. 4. 5.

Age below 40 years No major thoracic trauma No pulmonary or systemicinfections Normal chest radiograph Normal lung compliance: peak inspiratory pressure <2.7 kPa, tidal volume less than 15 ml kg -~ 6. Normal gas exchange (arterial partial pressure of oxygen > 15 kPa with fractional inspired oxygen of <30%) 7. Minimalinotropic requirements (dopamine or dobutamine < 10 ~g kg- ~min- i) 8. Normal electrocardiogram

Organ Procurement and Preservation Heart-lung transplant programmes were at first severely limited by the lack of availability of suitable donor organs and the problems of organ preservation. The criteria for donors are strict (Table 2), so that only 10-15 % of suitable heart donors will also be potential lung donors (14). Guidelines for the management of organ donation in patients declared brains dead have been drawn up for use in intensive care units (31). In the early stages the lack of a satisfactory lung perfusate necessitated moving the donor to the recipient hospital with resultant ethical and emotional problems and a further reduction in the potential donor pool. Research was directed at developing methods of preservation which would allow distant procurement and a number of such methods are now being used worldwide. One is the use ofcardiopulmonary bypass with profound hypothermia to cool the organs before harvesting (32), but this may cause lung injury during cardiopulmonary bypass. A second technique is autoperfusion of the heart-lung block during transportation (28). Perhaps the simplest method is the single pulmonary artery flush (33,34). PGI: is used to dilate the donor's pulmonary vascular bed before infusion of a colloid-based preservation solution. Using this method and with ischaemic times extending beyond

461

4 h, excellent early graft function has been achieved (33).

Diagnosis of Lung Rejection A major concern in the early series of HLT recipients was the development of obliterative bronchiolitis (35) which leads to disability and death in up to 50% of long term survivors after HLT (36). The aetiology of this process is closely related to the occurrence of repeated episodes of acute rejection which may be poorly responsive to intravenous steroid therapy (37). It was initially felt that rejection of the heart and lungs would occur simultaneously (38), and that endomyocardial biopsy, a well established method for diagnosing rejection in heart transplant recipients (39), could have a similar role in the HLT patient. However, experimental work by Cooper et al. (40) and clinical observations by the Stanford group (41) suggested that after HLT rejection in the lungs occurred earlier than in the heart and was more aggressive. A futher difficulty was that of distinguishing clinically between lung rejection and opportunistic infection (42). It became evident that in the HLT recipient rejection should be diagnosed by lung histology obtained using a reliable method. Transbronchial biopsy (TBB) through the fibreoptic bronchoscope, used in the diagnosis of interstitial lung disease, has been used successfully in HLT patients to diagnose rejection and to distinguish rejection from infection. It has a low morbidity (43). The characteristic histology of lung rejection is perivascular infiltrates consisting mainly of activated lymphocytes (44) (Plate 1). In diagnosing lung rejection TBB has a sensitivity of 70% and a specificity of 100% (43). By sampling all three lobes of one lung (lingula being regarded as a separate lobe) and taking at least four biopsies from each lobe this sensitivity may be further enhanced (45). As a result, endomyocardial biopsy is no longer necessary (46). Although in experienced hands TBB is a safe procedure, lung function monitoring is non-invasive and can be performed on a daily basis. It has been shown that acute lung rejection and infection are associated with a significant decline in forced expiratory volume in one second and in vital capacity (47) (Fig. 1). Monitoring of graft function by daily spirometry can provide an early indication for TBB which will then distinguish between rejection and infection (48).

Opportunistic Lung Infection Phlmonary infections occur frequently in HLT recipients (49,50). Although common, bacterial

462

Problems in Practice

Platel Transbronehial lung biopsy showing a dense lymphocyticperivascular infiltrate typical of acute rejection. Frequent alveolar macrophages are present in the adjacent parenchyma. (H & E, x 150). 120 I00

8o 6o v

4(3

ttt

R

R R

t

R

ILl la.

2(3 0

I 50

I 100

I 150

I 200

I 250

I :500

I 350

t 400

Days after transplant

Fig: 1 FEV~(% predicted) plotted against time after surgery for a representative-HLT patient. The times of rejection episodes are indicated by the arrows marked "R'.

pneumonias are usually diagnosed early and are rarely fatal. The major causes of morbidity and mortality are infections from viruses (particularly the herpes viruses), fungi and protozoa. Cytomegalovirus (CMV) infection was identified as early as 1964 as an important cause of death in renal allograft recipients (51). Primary organ-transmitted CMV disease Occurring in a seronegative recipient carries the highest risk ofdisability and death, particularly in the lung transplant patient (52). This form of infection can be effectively eliminated if seronegative recipients receive organs only from seronegative i:lonors. Even in lung transplantation this policy is controversial, because of concerns about the limited

donor pool. Treatment (Table 3) with the antiviral agent ganciclovir (Syntex, Berkshire, England) (52,53) of both primary infection and reinfection or reactivation has shown encouraging results and in the event of an inadvertent mismatch, CMV hyperimmune globulin (Biotest Pharma., Frankfurt, F.R.G.) (54) may prevent a fatal outcome. In contrast to CMV, herpes simplex virus (HSV) infection in solid organ transplants is almost never organ-transmitted. In the first reports of infection among HLT patients HSV was common, and HSV pneumonia had a fatal outcome (50). Prompt diagnosis by TBB and institution of treatment (Table 3) with intravenous acyclovir has resulted in clinical recovery in a number of instances (Smyth et al., unpublished). Patients who are seropositive are at risk and the greatest period of susceptibility is in the first 3 months after HLT. Oral acyclovir prophylaxis during this time may well prevent HSV infection and there is evidence that this drug may also provide prophylaxis against CMV infection (55). Pneumocystis carinii pneumonia (PCP) is reported to occur frequently following HLT (28). Prophylaxis, with low dose oral cotrimoxazole has been shown to eradicate this problem in renal transplant recipients (56). Occasionally cotrimoxazole is not tolerated, or is withdrawn because ofmyelotoxicity, and the patient is then at risk of PCP. Experience suggests that in HLT recipients PCP has a low fatality and responds well to treatment with intravenous sulphadimidine and trimethoprim (42).

Problems in Practice

463

Table3 Treatment ofpulmonary opportunistic infections in heart-lung transplant recipients. Doses may need to be reduced if renal function is impaired

Cytomegalovirus infection:

Prophylaxis Treatment

Herpes simplex virus infection:

Prophylaxis Treatment

Pneumocystis carinii pneumonia:

Prophylaxis Treatment

lnvasive aspergillosis:

Treatment

CMV hyperimmune globulin, 100 mg kg- ~weekGanciclovir, 5 rag kg- ~,2 daily Oral acyclovir, 200--400mg, 3 daily Intravenous acyclovir 5 mg kg-', 3 daily Oral cotrimoxazole, 480 rag, 2 daily Intravenous sulphadimidine, I g, 6 hourly Intravenous trimethoprim, 4-6 mg kg- ~day - ~in divided doses Intravenous amphoteficin B starting at 0.25 mg kg-~ day-m Increase to I mg kg-~ day- ~if tolerated, used with 100 ml of 20% mannitol to promote diuresis. Treat to total dose of 1"2-I "5 g

'~o

'

Plate 2 Transbronchial lung biopsy showing numerous megalic alveolar epithelial cells containing owls eye intra-nuclear and granular cytoplasmic inclusions. The appearances are characteristic ofcytomegalovirus infection. (H & E, x 2411).

Invasive aspergillosis carries a grave prognosis. In HLT recipients it occurs predominantly in transplanted lungs which have already suffered CMV infection, or in profoundly immunosuppressed individuals. Intravenous amphotericin B is effective in eradicating this infection, but only after a prolonged course to achieve a total dose of 1.2-1.5 g over 2-3 months. This is inevitably associated with irreversible renal impairment. A further concern is the observation that the decline in lung function associated with this infection is not reversible with treatment. The diagnosis of these infections requires bronchoscopy, bronchoalveolar lavage (BAL) and TBB.

Histology demonstrates alveolitis or pneumonia, and in addition the organism can often be identified. The characteristic viral inclusions of CMV and HSV may be seen on histological and cytological examination (Plates 2 and 3). Grocott's silver stain allows the trophozoites of Pneumocystis carinii or invading fungal hyphae to be identified (57). Inoculation of TBB and BAL specimens into MRC-5 cellsin tissue culture permits CMV and HSV infection to be identified by viral cultures, but diagnosis by this means may take man~y weeks. Recently the diagnosis of CMV using a fluorescent monoclonal antibody against the early CMV antigen (57) (detection early antigent fluorescent

464

Problems in Practice

Plate 3 Desquamated bronchial epithelium showing ballooning degeneration, intra-nuclear inclusions with halos and some ground glass nuclei. The bronchial lumen contains inflammatory cells and debris. The appearances are typical of necrotizing bronchitis due to herpes simplex. (H & E, x 240).

I 0 0 EX

80

-

--

~ rl

D

[]

0

0

[]

[]

D

D

O

D

n

D

60

n

> 40

0

20 ,|,,

74*/. I

I

I

63*/0 I

I

2

57°/* t

3

I

43*/* I

4

i

but fatal diseases, such as cystic fibrosis, has meant that is will soon become impossible to treat all suitable patients who are referred. Now that the difficulties with organ perservation have been overcome, the main challenge, in this form of transplantation, is to prevent the development o f chronic airflow obstruction which leads to death of the lung and probably is a consequence of recurrent rejection.

O

43*/. I

5

Acknowledgements

Year

Fig. 2 Actuarial survival curve with time after transpant for the first 66 HLT recipients in the Papworth series. Actuarial probability of survival for each year and corresponding confidence intervals are indicated.

Dr Smyth is supported by the Cystic Fibrosis Research Trust. We thank Mr Ben Milstein for his editorial comments and criticisms and Dr Colin Clelland for the histology illustrations.

focus or D E A F F test) has been shown to yield results within 24--48 h.

References

Conclusion

Transplantation of the lungs is now clinically possible using a variety o f techniques. It would appear to offer an appropriate treatment, in carefully selected recipients, for pulmonary vascular disease and a wide range of chronic lung diseases. F o r the first 66 patients in our group the actuarial probability of surviving to 1 y was calculated to be 74% and to 2 y 63% (Fig. 2). Indeed, the successful treatment of relatively common,

I. Demikov VP. Some essential points of the technique of transplantation of heart, lungs and other organs. In: Experimental Transplantation of Vital Organs. Moscow: Medgiz, State Press for Medical Literature, 1960; 29-48. 2. Lower RR, Stofer RC, Hurley EJ, Shumway NE. Complete homograft replacement of the heart and both lungs. Surgery 1961; 50: 842-845. 3. NakaeS, WebbWR, TheodoridesT, SuggWL. Respiratory function following cardiopulmonary denervation in dog, cat and monkey. Surg Gynaecol Obstet 1967; 125: 1285-1292. 4. Casteneda AR, Arnar O, Schimidt-Habelman P, Moiler JH, Zamora R. Cardiopulmonary transplantation in primates. J Cardiovasc Surg 1972; 37:523-53 I.

P r o b l e m s in P r a c t i c e

5. Van Buren CT. Cyclospodne: progress, problems and perspectives. Surg Clin North Am 1986; 66: 435-439. 6. Calne RY, White DJG, Thiru Set al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 1978; ii: 1323-1327. 7. Reitz BA, Burton NA, Jamieson SW et al. Heart and lung transplantation. Autotransplantation and allotransplantation in primates with extended survival. J Thorac Cardiovasc Surg 1980; 80: 360-372. 8. Reitz BA, Wallwork JL, Hunt SA et al. Heart-lung transplantation. Successful therapy for patients with pulmonary vascular disease. N Eng J Ivied 1982; 306: 557-564. 9. Hardy JD, Webb WR, Dalton ML, Walker GR. Lung homotransplantation in man: report of the initial case. J A M A 1963; 186: 1065-1074. 10. Morgan E, Lima O, Goldberg M et al. Improved bronchial healing in canine left lung reinplantation using omental pedicle wrap. J Thorac Cardiovasc Surg 1983; 85: 134-139. 1I. Goldberg M, Lima O, Morgan E. et al. A comparison between cyclosporin A and methylprednisolone plus azathioprine on bronchial healing following canine lung autotransplantation. J Thorac Cardiovasc Surg I983; 85: 821-826. 12. Toronto Lung Transplant Group. Unilaterallung transplantation for pulmonary fibrosis. N Engl J Med 1986; 314:1140--1145. 13. Cooper JD, Patterson GA, Grossman R, Maurer J. Double-lung transplant for advanced chronic obstructive lung disease. Am Rev Respir Dis 1988; 139: 303-307. 14. Harjula A, Baldwin JC, Starnes et al. Proper donor selection for heart-tung transplantation. The Stanford experience. J Thorac Cardiovasc Surg. 1987; 94: 874-880. 15. Penketh A, Higenbottam T, Hakim M, WaUwork J. Heart and lung transplantation in patients with end stage tung disease. Br M e d J 1987; 295:311-314. 16. Scott J, Higenbottam T, Hutter Jet al. Heart-lung transplantation for cystic fibrosis. Lancet 1988; ii: 192-194. 17. Smyth RL, Higenbottam TW, Scott JP et al. Early experience of heart-lung transplantation. Arch Dis Child (In Press). 18. Bourdillon PDV, Oakley CM. Regression of primary pulmonary hypertension. Br Heart J 1976; 38: 264-270. 19. Rich S, Levy PS. Characteristics ofsurviving and nonsurviving patients with primary pulmonary hypertension. Am J M e d 1984; 76: 573-578. 20. Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: a natural history and the importance of thrombosis. Circulation 1984; 70: 580-587. 21. Reeves JT, Groves BM, Turkevich D. The case for treatment of selected patients with primary pulmonary hypertension. Am Rev Respir Dis 1986; 134: 342-346. 22. Jones DK, Higenbottam TW, Wallwork J. Treatment of primary pulmonary hypertension with intravenous epoprostenol (prostacyclin). Br Heart J 1987; 57: 270-278. 23. Higenbottam TW, Spiegelhalter DJ, Scott JP, Fuster V, Caine N, Wallwork J. Survival in primary puimonary hypertension; a comparison of vasodilator treatment and heart-lung transplantation with the Mayo Clinic retrospective analysis of survival. Am Rev Respir Dis 1989; 139:A265 (Abstract). 24. McGavin CR, Artininti M, Nave H, McHardy G JR. Dyspnoea, disability and distance walked: Comparison

25.

26.

27. 28. 29. 30.

465

of estimates of exercise performance in respiratory disease. Br M e d J 1978; 2: 241-244. Wood A, Higenbottam T, Jackson M, Scott J, Stewart S, Wallwork J. Airway mucosal bioelectricpotential difference in cystic fibrosis after lung transplantation. Am Rev Respir Dis (In Press). Bishop JM, Cross KW. Physiological variables and mortality in patients with various categories of chronic respiratory disease. Bull Eur Physiopath Respir 1984; 20:. 495-500. Siassi B, Moss AJ, Dooley RR. Clinical recognition of cot pulmonale in cystic fibrosis. J Pediatr 1971; 78: 794-805. Griffith BP, Hardesty RL, Trento A e t ak Heart-lung transplantation: lessons learned and future hopes. Ann Thorac Surg 1986; 43: 6-16. Smyth RL, Scott JP, McGoldrick JP, Higenbottam TW, Wallwork J. Pneumothorax in cystic fibrosis. Ann Thorac Surg (In Press) (letter). Wallwork J, Williams R, Calne RY. Transplantation of liver, heart and lungs for primary biliary cirrhosis and primary pulmonary hypertension. Lancet 1987; ii: 182-185.

31. Rutter N, Mann NP, Watson AR. Organ Donation. Areh Dis Child 1989; 64: 875-878. 32. Baumgartner WA, Williams GW, Fraser CD et al. Cardiopulmonary bypass with profound hypothermia. An optimal preservation method for multiorgan procurement. Transplantation 1989; 47: 123-127. 33. Wallwork J, Jones K, Cavarocchi N, Hakim M, Higenbottam T. Distant procurement of organs for clinical heart-lung transplantation using a single flush technique. Transplantation 1987; 44: 654-658. 34. Hakim M, Higenbottam T, Bethune D et al. Selection and procurement of combined heart and lung grafts for transplantation. J Thorac Cardiovasc Surg 1988; 95: 474-479. 35. Burke CM, Theodore J, Dawkins KD et al. Posttransplant obliterative bronchiolitis and other late lung sequelae in human heart-lung transplantation. Chest 1984; 86: 824--829. 36. Burke CM, Theodore J, Baldwin JC et al. Twenth-eight cases of human heart-lung transplantation. Lancet 1986; i: 517-519. 37. Scott JP, Higenbottam TW, Clelland C et al. The natural history of obliterative bronchiolitisand occlusive vascular disease of patients following heart-lung transplantation. Transplant Proc 1989; 21: 2592-2593. 38. Reitz BA, Gaudiani VA, Hunt SA et al. Diagnosis and treatment of allograft rejection in heai't-lung transplant recipients. J Thorac Cardiovasc Surg 1983; 85: 354-361. 39. Caves PK, Stinson EB, Graham AF, Billingham ME, Grehl TM, Shumway NE. Percutaneous transvenous endomyocardial biopsy. J A M A 1973; 225: 288-291. 40. Cooper DKC, Novitzky D, Rose AG, Reichart BA. Acute pulmonary rejection precedes cardiac rejection following heart-lung transplantation in a primate model. JHeart Transplant 1986; 5: 29-32. 41. McGregor CGA, Baldwin JC, Jamieson SW et al. Isolated pulmonary rejection after combined heart-lung transplantation. J Thorac Cardiovasc Surg 1985; 90." 623-630. 42. Penketh AR, Higenbottam TW, Hutter J, Coutts C, Stewart S, Wallwork J. Clinical experience in the management of pulmonary opportunistic infection and

466

43.

44.

45.

46.

47.

48.

49. 50.

Problems in Practice

rejection in heart-lung recipients. Thorax 1988; 43: 762-769. Higenbottam T, Stewart S, Penketh A, Wallwork J. Transbronchial lung biopsy for the diagnosis of rejection in heart-lung transplant patients. Transplantation 1988; 46: 532-539. Hutter JA, Stewart S, Higenbottam T, Scott JP, Wallwork J. Histologic changes in heart-lung transplant recipients during rejection and at routine biopsy. J Heart Transplant 1988; 7: 440-444. Smyth RL, Scott JP, Igboaka G, Clelland C, Higenbottam TW, Wallwork J. Distribution of rejection within the transplanted lung. Thorax 1989; 44: 321P (Abstract). Higenbottam T, Hutter JA, Stewart S, Wallwork J. Transbronchial biopsy has eliminated the need for endomyocardial biopsy in heart-lung recipients. J Heart Transplant 1988; 7: 435-439. Otulana BA, Higenbottom TW, Scott JP, Clelland C, Hutter JA, Wallwork J. Pulmonary function monitoring allows diagnosis of rejection in heart-lung transplant recipients. Transplant Proc 1989; 21: 2583-2584. Otulana BA, Higenbottam TW, Ferrari L, Scott J, Wallwork J. The use of home spirometry in detecting acute lung rejection and infection following heart-lung transplantation.Chest (In Press). Dummer JS, Montero CG, Griftith BP, Hardesty RL, Paridis IL, Ho M. Infections in heart-lung transplant recipients. Transplantation 1986; 41: 725-729. Brooks RG, Hofflin JM, Jamieson SW, Stinson EB, Remington JS. Infectious complications in heart-lung transplant recipients. Am J Med 1985; 79:412-422.

51. Hill RB, Rowlands IT, Rifkind D. Infectious pulmonary disease in patients receiving immunosuppressive therapy for organ transplantation. N Engl J Med 1964; 171: 1021-1027. 52. Hutter JA, Scott J, Wreghitt T, Higenbottam T, Wallwork J. The importance of cytomegalovirus in heart-lung transplant recipients. Chest 1989; 95: 627-63 I. 53. Keay S, Peterson E, Icenogle T et aL Ganciclovir treatment of serious cytomegalovirus infection in heart and heart-lung transplant recipients.Rev hTf Dis 1988; 10, $563-$57 I. 54. Snydman DR, Werner BG, Heinze-Lacey Bet al. Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal transplant recipients. N Engl J Med I987; 317: 1049-1054. 55. Balfour HH, Chace BA, Stapleton JT, Simmons RL, Fryd DS. A randomised, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N EngtJ Med 1989; 320: I381-1387. 56. Higgins RM, Bloom SL, Hopkin JM, Morris PJ. The risks and benefits of low dose cotrimoxazole prophylaxis for Pneumocystis pneumonia in renal transplantation. Transplantation 1989; 47: 558-560. 57. Griffiths PD, Panjwani DD, Stirk PR et al. Rapid diagnosis of cytomegalovirus infection in immunocompromised patients by detection of early antigen fluorescent loci. Lancet 1984; ii: 1242-I 245.