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Combined heart-lung transplantation is the optimal treatment option for many patients with end-stage heart failure and fixed severe pulmonary hypertension. It offers the only possibility of long-term survival and a return to a normal quality of life. Unfortunately, it is rarely performed because of donor organ allocation policies. We present the case of a critically ill 24-year-old man, who after waiting for >100 days in-hospital on the urgent transplant list, deteriorated further and underwent the first successful heart-lung transplant with organs from a donation after circulatory death., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Infective endocarditis is a rare but life-threatening complication of heart and heart-lung transplantation. We describe a 32-year-old woman who developed aortic valvular endocarditis following heart-lung transplantation. Enterococcus was the infective organism. The patient's condition was successfully managed using prolonged intravenous antibiotic therapy and aortic valve replacement.

Background: Heart-lung transplantation (HLT) for Eisenmenger syndrome (ES) provides superior early and intermediate survival when compared with other forms of transplantation. The early risk factors and long-term outcome of HLT for ES are less well defined., Methods: We analyzed 263 patients who had undergone HLT at our institution during more than 15 years. Fifty-one consecutive patients with ES who underwent HLT, 33 (65%) of which had simple anatomy, were compared with 212 cases having HLT for other indications (non-ES)., Results: Female sex and previous thoracotomy were more prevalent in the ES group. Patients with ES had greater postoperative blood loss and returned more frequently to the operating room for control of bleeding. There were 8 (16%) early deaths in the ES group compared with 27 (13%) in non-ES (p = 0.65). One-, 5-, and 10-year survival rates for ES were 72.6%, 51.3%, and 27.6%, respectively, compared with non-ES of 74.1%, 48.1%, and 26.0%, respectively, and there was no difference in survival overall (p = 0.54). Among ES patients, previous thoracotomy was a risk factor for hospital death. A subgroup analysis based on simple versus complex type of ES did not show statistically significant differences in terms of postoperative course or early or late survival., Conclusions: Heart-lung transplantation is a successful procedure for ES. Despite a greater frequency of risk factors and a more difficult operative course, early and late outcome with HLT is comparable to non-ES recipients.

Cytomegalovirus (CMV) disease has had a significant clinical impact on the heart, heart-lung and lung transplant recipients in our centre. CMV disease has been so severe with CMV antibody-negative heart-lung transplant patients receiving organs from CMV antibody-positive donors (CMV-mismatched patients) that in 1986 we adopted the policy of not transplanting CMV-positive organs into CMV-negative heart-lung or lung recipients. In December 1992, we instituted a policy of providing intravenous ganciclovir (5 mg/kg twice a day for 28 days) during the immediate postoperative period for CMV-mismatched heart recipients and CMV antibody-positive heart-lung and lung patients, who have been the patients at greatest risk of severe CMV disease in our centre. A placebo group was not employed because of ethical considerations, ganciclovir having been shown to be effective for the treatment of CMV infections among transplant patients. Compared with a historical control group of patients receiving no prophylaxis, prophylactic ganciclovir reduced the incidence of CMV infection (39 % vs 91 %, P = 0.0006) and CMV disease (17 % vs 74 %, P = 0.0004) among CMV antibody-positive heart-lung recipients. Prophylactic ganciclovir did not significantly reduce the incidence of CMV infection or disease among heart or isolated lung recipients. Ganciclovir was well tolerated, with few adverse reactions. In the case of heart-lung transplant patients, one month of intravenous prophylactic ganciclovir significantly reduced the incidence of both CMV infection and disease when compared with patients who received no prophylaxis. With the lung transplant and heart transplant patients, there were no significant differences between the prophylaxis and nonprophylaxis groups, although there was a consistent trend towards less infection and disease in the prophylaxis groups.

More than 1,200 patients have now undergone thoracic transplantation at Papworth Hospital and about 90 transplants are performed annually. Papworth remains one of the largest transplant units in the UK. Unique activities include a very large heart-lung transplant program: 247 patients have now undergone heart-lung transplants and 73 domino heart transplants have been performed. The 5-year survival rates are 71% for heart transplants, 48% for heart-lung and 41% for lung transplants, respectively. Chronic obliterative bronchiolitis remains an important limitation for heart-lung and lung transplant survival.

The case history is presented of a patient with common variable immunodeficiency in whom heart lung transplantation has been carried out with success. Transplantation was the only long term therapeutic option in this patient due to the progressive respiratory failure resulting from bronchiectasis, emphysema, and granulomatous lung disease.

Transbronchial biopsies (TBBs) are useful to diagnose acute rejection and infection in patients with lung transplants. The value of routine surveillance biopsies (S-TBBs) is not known, and such biopsies with a clinical indication are not without risk and are expensive. One hundred twenty-six 6-mo survivors of heart-lung transplantation (HLT) were studied to determine the effect of stopping S-TBBs on the development of bronchiolitis obliterans syndrome (BOS) and subsequent survival. Fifty-one received transplants while S-TBB was part of routine care (group A), and 75 received transplants after this practice was stopped (group B). There was no difference in patient characteristics. Group A had shorter graft ischemia (p < 0.01) and longer postoperative ventilation (p < 0.01). Maintenance immunosuppression was similar, but group A had more steroid pulses in the second 6 mo after HLT (p < 0.01). The number of patients free from any functional deterioration at 49 to 60 mo after HLT declined to 39% in group A and 64% in group B. The risk of developing BOS grade 1 in group A relative to group B was 1.63 (95% confidence intervals: 0.96-2.79, p = 0.07). Patient survival was similar in the two groups. A total of 86 TBBs were taken in the absence of any signs or symptoms and had low diagnostic yield. In summary, there was no increased incidence of BOS after stopping S-TBBs.

We have attempted to quantify the optimal clinical use of cyclosporine during the first 3 months after heart-lung transplantation. We used multiple logistic regression to investigate the influence of blood cyclosporine concentrations and other potential risk factors on histologically confirmed acute lung rejection in 50 heart-lung transplant recipients. A 50% increase in cyclosporine concentration was associated with a 25% reduction in risk of rejection in the subsequent 5 days (P=0.008). Increasing oral corticosteroid dose also protected against rejection (P=0.006). Rejection was over 4 times more likely to occur during the first 20 postoperative days (P=0.002). After 20 days, an FEV1 < or = 70% of the age-, sex-, and height-adjusted expected score was associated with a 4-fold increase in risk of rejection (P=0.01). Patients who had multiple previous rejection episodes were also predisposed to further rejection (P=0.005). An investigation of threshold levels for the cyclosporine concentration-effect relationship suggested that cyclosporine concentrations above 500 microg L(-1) provide optimal protection against acute lung allograft rejection. This result provides an objectively defined therapeutic threshold for targeting early cyclosporine concentrations following heart-lung transplantation.

We have attempted to determine the optimal clinical use of cyclosporine during the first 3 months after heart transplantation. We used multiple logistic regression to quantify how blood cyclosporine concentrations and other potential risk factors influence the risk of histologically confirmed acute rejection in 111 heart transplant recipients. A 50% increase in cyclosporine concentration was associated with a 15% reduction in risk of rejection in the subsequent 5 days (P=0.002). Increasing oral corticosteroid dose also protected against rejection (P=0.01). Rejection was over 2.5 times more likely during the first 20 postoperative days, and patients with 2 HLA-DR mismatches who were transplanted for cardiomyopathy or who had multiple previous rejection episodes were predisposed to further rejection (P<0.01). High short-term variability in cyclosporine concentrations was weakly associated with risk of rejection (P=0.1). Investigation of threshold levels for the cyclosporine concentration-effect relationship suggested that concentrations above 375 microgram L(-1) provide optimal protection against acute cardiac allograft rejection. This result yields an objectively defined therapeutic threshold for targeting early cyclosporine concentrations following heart transplantation, although the upper end of the range will depend on the individual's susceptibility to nephrotoxicity and infection.

Background: The measurement of the quality of the outcome of treatment as viewed by patients is becoming increasingly recognized as an important aspect of decision making in all health services. This major study, which set out to measure the health-related quality of life outcomes of heart and lung transplantation, developed from the experience gained in the United Kingdom and United States studies of the cost and benefits of heart transplantation in the 1980s., Methods: The design was prospective with a cohort of patients completing a variety of generic and specific health-related quality of life questionnaires at intervals before and after heart and lung transplantation. The sample size was not prescribed; one of the aims of the project was to test the feasibility of introducing routine monitoring of health-related quality of life outcomes as an integral part of a developing transplant service., Results: Before the operation, there was evidence of deterioration over time in all dimensions of the Nottingham Health Profile. In comparing Profile scores at less than 3 months before with those at 3 to 6 months after transplantation, statistically significant improvements were evident (p < 0.001). Mean scores at intervals up to 2 years after transplantation showed little change over time and compared well with those from a general population sample. Hospital Anxiety and Depression Scale scores were reduced significantly (p < 0.01) by 1 year after heart and lung transplantation. In the pretransplantation period, at least 90% of 101 patients had some level of restriction in home and leisure activities, reducing to between 2% and 24% at 1 year after transplantation. Similarly, 79 patients (78%) had chest pain, and 101 (100%) were breathless before transplantation, reducing to 54% and 39%, respectively, at 1 year after surgery; by which time, for 8 of 10 patients, the problem was occasional., Conclusions: Highly significant improvements were observed in the physical, social, and emotional dimensions of health-related quality of life of patients after heart-lung transplantation. The advantages and feasibility of combining generic and condition-specific questionnaires are shown together with the need to develop new measures with greater sensitivity to the smaller peaks and troughs of recovery.

Given the internationally recognized definition of bronchiolitis obliterans syndrome (BOS) and longer follow up of heart-lung transplant recipients, it is possible to establish some of the major risk factors for development and progression of BOS. Between April 1984 and 31 December 1993, 157 patients underwent heart-lung transplantation; 126 survived at least six months after operation and so were at risk of developing BOS. The following early risk factors were assessed for development of BOS grade 1 (21-35% decline in FEV1) and progression from grade 1 to grade 2 (36-50% decline in FEV1): age, gender and underlying diagnosis of the recipient, evidence of acute rejection and cytomegalovirus (CMV) infection within 6 months of operation, peak FEV1 achieved, age and gender of the donor, cold ischemic time of the graft, and matching of CMV serological status and HLA antigens of donor and recipient. The number of acute rejection episodes observed remained the single most important determinant of development of BOS grade 1 (relative risk 1.17 (1.06, 1.29), P=0.002) and progression to BOS grade 2 (relative risk 1.58 (1.02, 2.46), P=0.03). No other factors were significantly related to development or progression of BOS, although both evidence of CMV infection and disease and the number of HLA mismatches increased the risk. Bronchiolitis obliterans syndrome is a major problem for medium-to-long-term survivors of cardiothoracic transplantation. Acute rejection early after transplantation is a sensitive prognostic indicator of subsequent functional decline and requires prompt attention.

A critical, worldwide shortage of thoracic organs exists. The donor management program at Papworth Hospital, National Health Service Trust, Cambridge, United Kingdom, allows satisfactory transplantation of thoracic organs that initially appear unsuitable. The perioperative organ retrieval team members assess the cardiovascular status of all potential donors and manage suboptimal hemodynamics with hormonal replacement therapy consisting of triiodothyronine, antidiuretic hormone, epinephrine, and insulin. These donors' cardiovascular and pulmonary functions must be within acceptable limits at the time of organ excision. Our standardized approach facilitates objective decision making regarding the appropriate use of donor organs and has increased the number of available donor organs at Papworth Hospital by 30%. Morbidity and mortality rates in thoracic organ recipients have not increased since the authors developed the standardized approach, and more patients have benefited from thoracic organ transplantation.

Objective: Domino cardiac transplantation affords flexible and optimal organ utilization, provides hearts unaffected by brain death, allows prospective tissue matching, and subsequent transplantation with short allograft ischemic times. A retrospective review of our experience with domino cardiac transplantation has been made., Methods: Seventy-two of 119 patients who underwent heart-lung transplantation from 1988 on served as domino cardiac donors (40 males, 32 females; mean age of 32 years; mean weight of 51 kg). The domino donor diagnoses were cystic fibrosis (n = 47), bronchiectasis (n = 9), primary pulmonary hypertension (n = 6), emphysema (n = 7), pulmonary fibrosis (n = 2) and Eisenmenger's syndrome (n = 1). Forty-seven domino hearts were transplanted at our institution and 25 were exported to other centres in the United Kingdom. The 72 domino cardiac recipients were 62 males and 10 females, mean age of 47 years, mean weight of 60 kg, with ischemic heart disease (n = 32), cardiomyopathy (n = 36) and other conditions (n = 4)., Results: There were four deaths (5.6%) at less than 30 days (2 from multiple organ failure, 1 from primary allograft failure and 1 from acute rejection). Actuarial survival estimates and 1 and 5 years were 77 +/- 5.2% nd 69 +/- 6.3%, respectively. This compared favourably with survival data obtained in 234 non-domino cardiac recipients. In the patients transplanted at Papworth, there was no difference in the incidence of rejection (0.6 +/- 0.05 versus 0.7 +/- 0.03 events per 100 patient days for the first 12 months) or in the freedom from graft atherosclerosis (74 +/- 3% versus 70 +/- 3% at 5 years) between the domino and non-domino groups., Conclusions: The use of domino hearts donated by recipients of heart-lung transplants is beneficial and is associated with an excellent early and longer-term outcome.

With the increasing number of successfully performed lung transplants and a longer follow up of patients, there is an interest in the analysis of long-term complications and their impact on patient survival. Heart-lung transplantation was performed in 157 patients with 126 patients surviving at least 6 months. Early death was mainly caused by bacterial and viral infection. Long-term patient survival was decisively influenced by obliterative bronchiolitis. With the new international definition of bronchiolitis obliterans syndrome (BOS) based on an irreversible decline of FEV1 from baseline values, it became possible to analyse the incidence of BOS and the impact on patient mortality in long-term survivors. FEV1 reached a peak value of 102% predicted at a median of 219 days. In 106 of 126 patients (84%), FEV1 showed no decline within the first year. A total of 60 patients (47.6%) developed BOS grade 1 with progression to BOS grade 2 in 85% of these patients. The incidence of BOS was 12.6% at 1 year increasing to more than 50% 5 years after transplantation. Patient mortality due to obliterative bronchiolitis increased from 1% at 1 year to 18% more than 5 years after transplantation. Almost all deaths (86%; 32/37) more than 1 year after HLT were associated with bronchiolitis obliterans. In summary, bronchiolitis obliterans decisively contributes to long-term patient morbidity and mortality after heart-lung transplantation. Clinical and research efforts should be directed towards avoiding this important complication.

Background: Lung transplantation is performed for an increasing range of pulmonary conditions in which the diagnosis is often clinical or based on limited biopsy material. Diagnosis may be made late in the course of the disease where specific features are no longer present. Posttransplantation complications and disease recurrence may relate to the primary disease, and accurate diagnosis is therefore essential., Methods and Results: A pathologic review of 183 explanted lungs over a 10-year period (heart-lung = 109, single lung = 65, double lung = 9) showed 29 significant discrepancies or additional features likely to effect outcome. The final pathologic diagnosis was cystic fibrosis (n = 66), emphysema (59), bronchiectasis (17), pulmonary fibrosis (19), sarcoidosis (10), Langerhans cell histiocytosis (3), pulmonary veno-occlusive disease (3), posttransplantation obliterative bronchiolitis (2), primary hemosiderosis (1), rheumatoid obliterative bronchiolitis (1), extrinsic allergic alveolitis (1), pneumoconiosis (1). Unsuspected diagnoses included tuberculosis (8) (four cases of which were active and in single lung recipients requiring antituberculous chemotherapy), sarcoidosis (9), (of which, six were unsuspected primary diagnoses and three were additional diagnoses), veno-occlusive disease (3), carcinoma (1), pneumoconiosis (1), and pulmonary fibrosis (2). Aspergillus infection (2) and bronchocentric granulomatosis (3) were found in patients with cystic fibrosis. One active tuberculosis case also showed an aspergilloma. Unsuspected infections requiring therapy in immunosuppressed patients and previously unsuspected sarcoidosis, which is known to recur in the graft, were the major novel diagnoses. Discrepancy rate was 12 of 65 in single lungs (19%) and 17 of 109 in heart-lungs (16%)., Conclusions: These results emphasize the need for accurate preoperative diagnosis especially when the similarly diseased native lung remains in situ.

Background: A retrospective serologic study was made of 67 heart-lung and 295 heart transplant recipients (with transplantations at Papworth Hospital, Cambridge, England) to determine the incidence and clinical impact of Epstein-Barr virus infection., Methods: Epstein-Barr virus capsid antigen immunofluorescence tests were performed, and the antibody avidity was determined by modifying the washing procedure to include a mild reducing agent (8M urea)., Results: This testing showed that 6.0% of the patients had primary Epstein-Barr virus infections, whereas 17.4% had the reactivation of a past infection. Primary infections were only detected in patients who were Epstein-Barr virus antibody-negative before transplantation, who had received an organ from an Epstein-Barr virus antibody-positive donor. Of the patients with serologically proven Epstein-Barr virus infections, 52.9% had symptoms. Although these were generally mild, five heart and two heart-lung transplant recipients had malignant lymphoma and one heart and one heart-lung transplant recipient had lymphoproliferative disease after Epstein-Barr virus infection. Additional four heart transplant recipients had lymphoma after transplantation. None of these four patients had evidence of active Epstein-Barr virus infection; one was Epstein-Barr virus antibody-negative during the study period and three had stable Epstein-Barr virus virus capsid antigen immunoglobulin G titers throughout., Conclusions: Epstein-Barr virus infection in organ transplant recipients may lead on to life-threatening lymphoproliferative disease or lymphoma. For this reason it may be beneficial to monitor patients after transplantation for evidence of Epstein-Barr virus infection and to follow the progress of those affected.

Background: Donor management remains one of the most neglected areas of transplantation. A comprehensive donor management regimen has been developed. The results of the application of this strategy form the basis of this report., Methods: Full hemodynamic data were collected from 150 multiorgan donors between October 1990 and August 1993. The data were collected at the time of donor team arrival, after insertion of a pulmonary artery floatation catheter and immediately before cardiac excision., Results: Fifty-two donors (35%) fell well outside our minimum acceptance criteria on arrival. Twenty-one of fifty-two had a mean arterial pressure less than 55 mm Hg (mean 47 mm Hg) despite inotropic support in most cases; 10 of 52 had a central venous pressure greater than 15 mm Hg (mean 18.0 mm Hg); 2 of 52 had a high inotrope requirement greater than 20 micrograms/kg/min (mean 25 micrograms/kg/min). After the insertion of a pulmonary artery floatation catheter, an additional 13 of 52 donors were found to have a pulmonary capillary wedge pressure greater than 15 mm Hg (mean 19.8 mm Hg), and the final 6 of 52 had a low left ventricular stroke work index, less than 15 gm (mean 12.8 gm). After optimal management, including hormone replacement 44 of 52 donors yielded transplantable organs (29 hearts, 15 heart and lung blocks). Thirty-seven of forty-four patients (84%) were alive and well from 13 to 48 months after transplantation. There were five early deaths (11%) caused by infection (heart), adult respiratory distress syndrome (heart), arrhythmia (heart), cerebrovascular event (heart and lung), and infection (heart, lung, and liver). Two late deaths (5%) occurred as a result of tamponade (3 months, heart) and infection (14 months, heart and lung). Eight of fifty-two organs were still unsuitable for transplantation after optimum management during the splanchnic dissection as a result of inotrope dependency (n = 4), left ventricular hypertrophy (n = 2), and coronary artery disease (n = 2)., Conclusions: The data indicate that, of the organs which initially fall outside our transplant acceptance criteria, 92% are capable of functional resuscitation. Conversely, superficial assessment may not show compromised function. Optimizing cardiovascular performance also has important implications for the viability of all transplantable organs. This aggressive approach to donor management has resulted in the transplantation of 44 donor hearts that may otherwise have been turned down or inappropriately managed.

Heart-lung transplantation in the presence of complex congenital heart disease including situs inversus and significant chest wall deformity can be accomplished successfully. However, the postoperative course is apt to be prolonged because of mechanical respiratory problems, which will respond to a protocol of weaning and nutritional supplementation.

Lung volumes after heart-lung transplantation (HLT) were recorded and compared with measurements at the time of assessment for surgery and the predicted values for recipients. The influence of donor lung size and recipients' underlying lung disease was evaluated. All patients underwent HLT between April 1984 and April 1991, and only those 82 who survived for at least 6 mo were studied. Mean total lung capacity (TLC) at preoperative assessment was 112% (SD = 28%) of the value predicted for recipients. One month after HLT, mean TLC was 83% (SD = 15%) of the predicted value but increased to 100% (SD = 15%) after 9 mo. No further change in average TLC occurred for 5 yr subsequently. The mean TLC of patients with emphysema before surgery was 164% (SD = 26%) of the predicted value and fell to the predicted value within 1 mo of HLT. The TLC in patients with primary pulmonary hypertension before surgery was close to the predicted value, but postoperative predicted TLC was achieved later than in emphysema patients. A donor-versus-recipient difference in TLC of more than 1L at the time of assessment did not influence the adaptation to the predicted value. FEV1 and vital capacity (VC) rose from means of 70% (SD = 25%) and 63% (SD = 20%) at 1 mo to 96% (SD = 27%) and 91% (SD = 18%), respectively, at 9 mo after HLT. After HLT, TLC returns to the predicted value for the recipient, and not to the preoperative TLC.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of donor hearts from heart-lung recipients, the so-called domino procedure, began at Papworth Hospital in November 1988. Between then and September 1992, 198 heart transplantations and 86 heart-lung transplantations were performed. Fifty-three heart-lung recipients donated their hearts for use in the domino procedure. Thirty-two domino hearts were transplanted at Papworth and 21 were exported to other centers. Institution of the domino procedure allowed us to perform 19% more heart transplantations (166 to 198) than would have been done had the procedure not been used. The ischemic time was significantly shorter for the domino hearts compared with organs from brain dead donors (134 minutes versus 191 minutes; p < 0.001). No difference was found in the 3-month (84% versus 83%) or 1-year (74% versus 76%) survival between domino and nondomino recipients. Other potential advantages of the domino procedure include detailed pretransplantation evaluation of the heart in live donors and the potential for human leukocyte antigen matching. Additionally many heart-lung recipients have elevated pulmonary artery pressures and a "conditioned", hypertrophied right ventricle. The use of such hearts for heart transplantation has theoretic appeal for patients with elevated pulmonary vascular resistance.

Between August 1982 and December 1992, 260 patients were accepted for heart and lung transplantation, of whom 139 patients underwent transplant surgery. One hundred twenty-one patients have not received transplants, of whom 80 have died, four were transferred to other lists, and 37 were still waiting for suitable organs at the close of the study. Median waiting time for those patients who underwent heart and lung transplantation was 7 months, whereas patients who died waiting spent a median of 5 months on the list. Recipients are matched to donor organs according to blood type, size (total lung capacity), and cytomegalovirus antibody status. These factors, along with age, gender, underlying diagnosis, and Toxoplasma antibody status, were studied to assess their influence on survival after acceptance and time to transplantation. The only characteristic that significantly influenced survival after acceptance was the underlying disease, with patients with Eisenmenger's syndrome having significantly longer survival than the other groups (relative risk = 0.21; p < 0.001). Patients with Eisenmenger's syndrome underwent transplantation at a slower rate than did other patients (relative risk = 0.51; p = 0.012). Patients who had a total lung capacity of more than 6 L underwent transplantation significantly more quickly than did smaller patients (relative risk = 1.98; p = 0.005). Male patients underwent heart and lung transplantation at a quicker rate than did female patients (relative risk = 1.86; p < 0.001), although this was related to size. Patients who had cytomegalovirus-positive antibodies underwent transplantation at almost twice the rate of patients who had cytomegalovirus-negative antibodies (relative risk = 1.92; p < 0.001). Age at acceptance, blood type, and Toxoplasma status did not significantly influence time to heart and lung transplantation. In summary, cytomegalovirus antibody status, patient size, and gender significantly affect the waiting time to heart and lung transplantation. Patients with Eisenmenger's syndrome wait longer than other patients as a result of the natural history of their disease.

As the numbers of heart and lung transplant recipients have increased it has become possible to identify major risk factors for early (within 3 months) and later (after 3 months) death after this procedure. For 100 patients receiving organs between April 1984 and February 1991, and followed up until February 1992, patient characteristics, operative details, and early morbidity were assessed for their effects on early and later deaths. Recipient age, sex, and preoperative diagnosis did not have a significant effect on early (within 3 months) or later death. Positive cytomegalovirus antibody status of donor or recipient conferred greater risk of death within 90 days (odds ratio [OR] = 3.24, P = 0.06). Greater than 2 L blood in the first 24 hr after operation (OR = 6.00, P = 0.05), and ventilation for greater than 24 hr (OR = 4.87, P = 0.006) were significant prognostic indicators of early death. After the first 3 months, the main risk factor for death was rejection in the first 3 months (OR = 1.38 per episode, P = 0.008). Early infection in general and CMV infection in particular were associated with a small increase in risk. This study confirms the importance of matching donor and recipient for CMV and shows that difficulties during operation, reflected in postoperative bleeding and ventilation times increased the chance of early death. Later death was associated with early acute rejection. A detrimental effect of infection, including CMV infection, either does not exist, or is too small to be detected in a study of this size.

Obliterative bronchiolitis (OB) continues to be a major cause of morbidity and mortality following heart-lung transplantation. We compared the incidence of death from obliterative bronchiolitis in 19 children and 72 adults following heart-lung transplantation at our institutes. The incidence of death from OB at 2 years was 38% for children compared with 17% for adults, this difference was significant (Cox-Mantel Z value = 2.243, P < 0.05). The frequency of acute lung rejection and persistent lung rejection, previously described as risk factors for OB in adults, were significantly more common in children, P = 0.004 and P = 0.001, respectively. Average forced expiratory volume in 1 s was lower in children than in adults for each 3-month period after transplantation (P < 0.001). In conclusion, identified risk factors for the development of OB were more common, and the risk of death from OB was greater in children than in adults following heart-lung transplantation.

Bronchoalveolar lavage levels of elastase were assayed to determine the timing and magnitude of elevations in elastase relative to both fibrosis, as indicated by hyaluronate (HA) levels, and decline in FEV1 characteristic of the clinical syndrome of obliterative bronchiolitis (OB). Samples were collected from 48 heart-lung or single lung transplant recipients. Regression analysis was performed and demonstrated that high levels of elastase occurred with active decline in lung function and in association with high levels of HA. This study suggested that intense neutrophil elastase release occurs concurrent with the development of OB and may contribute to the destruction of bronchiolar architecture.

Between June 1988 and February 1993, combined heart-lung transplantation was performed in 30 children and adolescents aged 3.6 to 18.6 years (mean, 12.2 years) at The Hospital for Sick Children in London. Original diagnoses included cystic fibrosis (n = 25), Eisenmenger's syndrome (n = 4), and chronic graft-versus-host disease of the lung (n = 1). Posttransplantation maintenance immunosuppression comprised a triple regimen, with methylprednisolone and antithymocyte globulin given perioperatively and for episodes of allograft rejection. Actuarial survival was 63% (95% confidence interval: 42%-78%) at 1 year and 48% (95% confidence interval: 27%-66%) at 3 years. Obliterative bronchiolitis has been diagnosed in 13 patients (43%). Actuarial freedom from obliterative bronchiolitis in survivors was 76%, 59%, and 37% at 12, 24, and 36 months after transplantation, respectively. Recipients in whom obliterative bronchiolitis developed within the first year (n = 6) had more episodes of pulmonary rejection during the first 6 months after transplantation (mean, 5.7 episodes per patient) than those in whom "premature" obliterative bronchiolitis did not develop (mean, 3.2 episodes per patient). Infection of the pulmonary allograft was implicated to a lesser extent in predisposing to obliterative bronchiolitis. At 2, 3, and 6 months, tracheal stenosis developed in three patients, all of whom died with obliterative bronchiolitis within 10 months of transplantation. Noncompliance with therapy was considered a contributory factor in producing obliterative bronchiolitis in four adolescent recipients. The high incidence of obliterative bronchiolitis observed in this pediatric cohort may have a multifactorial cause.

We have studied the effects on FEV1 of inhaled capsaicin in concentrations of 3 x 10(-6) to 3 x 10(-1) mg/ml and methacholine (1 to 16 mg/ml) in 15 heart-lung transplant (HLT) patients who had undergone recent transbronchial lung biopsy to determine the relationships in chronically denervated lungs between these different forms of airway hyperreactivity and inflammation. A total of 10 normal subjects and 17 asthmatic subjects were included for comparison. Capsaicin caused bronchodilation in eight HLT patients (FEV1 rising by 6.4 to 26.8%) and bronchoconstriction in two (fall in FEV1 of 7.2 and 7.6%). By contrast, seven asthmatic subjects developed bronchoconstriction after capsaicin (fall in FEV1 5.6 to 40.4%); the remaining 10 asthmatic subjects showed no response. Bronchial hyperresponsiveness to methacholine was most evident in the asthmatic subjects, but six HLT patients demonstrated a > or = to 20% fall in FEV1 with < or = 8 mg/ml of methacholine. All normal subjects were nonresponsive to both agents, and all normal and asthmatic subjects, unlike HLT patients, coughed with capsaicin. No relationship existed between the methacholine and capsaicin responses. In the HLT patients neither form of airway responsiveness was related to the degree of inflammation seen on transbronchial lung biopsy. The results suggest that in normal subjects, although it provokes cough, inhaled capsaicin causes little airway narrowing.(ABSTRACT TRUNCATED AT 250 WORDS)

Between October 1985 and July 1992 we performed heart-lung transplantation in 42 patients with end-stage respiratory disease caused by cystic fibrosis. Twenty-eight of these patients are alive at 3 months to 7 years after heart-lung transplantation. Actuarial survival at 1 year and 3 years after transplantation was 78% and 65%, respectively, in this group, which compares favorably with 77% and 60%, respectively, in patients without cystic fibrosis undergoing heart-lung transplantation. Similarly no significant difference was found in the incidence of postoperative infections between patients with cystic fibrosis and patients without cystic fibrosis undergoing heart-lung transplantation. Quality of life indexes analyzed by the Nottingham Health Profile reveal significant improvements for patients surviving longer than 3 months from surgery. Long-term survival is determined by the development of obliterative bronchiolitis, which has occurred in 11 patients, six of whom have died. Early postoperative survival appears to be compromised by poor preoperative nutritional status. The study provides evidence that patients with end-stage respiratory disease caused by cystic fibrosis gain a survival advantage and improvement in quality of life after heart-lung transplantation when compared with patients who do not receive this form of therapy.

Objective: To determine whether epoprostenol (prostacyclin, PGI2) or heart-lung transplantation (HLT), or both improves survival of patients with severe pulmonary hypertension., Design: This was a prospective study where the effects of epoprostenol were compared with conventional treatment. Also, the benefits of epoprostenol and HLT were assessed by comparing survival in this group with that of 120 patients at the Mayo Clinic before HLT and epoprostenol treatment became available., Patients and Interventions: Forty four patients were studied; 25 received continuous epoprostenol over a four year period (mean (SD) cardiac index 1.8 (0.4) 1 min-1 m-2 and mean (SD) pulmonary artery pressure (PAP) 70 (16) mm Hg) and 19 did not (cardiac index 2.1 (0.6) 1 min-1 m-2 and PAP 64 (13) mm Hg). Ten patients underwent HLT: seven had received epoprostenol, and three had not., Results: The therapeutic intervention with epoprostenol, or HLT, or both improved survival compared with the Mayo clinic patients (p = 0.05). Most of the benefit was conferred by epoprostenol, which prolonged survival twofold from a median time of eight to 17 months and doubled the changes of successful HLT. The improved survival with epoprostenol was not related to its immediate capacity to cause pulmonary vasodilation. Those patients who had limited acute pulmonary vasodilation when treated with epoprostenol showed the greatest improvement in survival., Conclusions: These preliminary results indicate that those pulmonary hypertensive patients with the poorest chance of survival can be helped by epoprostenol and by HLT.

Heart-lung transplantation is a successful treatment for patients with cystic fibrosis and chronic respiratory failure. Patients are assessed for surgery when life expectancy is deemed short. This study assesses the ability of measurements of pulmonary function, blood gas levels, and nutritional status to predict survival of patients awaiting heart-lung transplantation and to assess the effect of heart-lung transplantation on survival. Sixty-seven patients with cystic fibrosis were accepted for heart-lung transplantation from 1985 through 1990. Each patient underwent tests of pulmonary function, exercise tolerance, blood-gas levels, and nutritional status. Cox regression was used to analyze the prognostic value of these data. Of the 67 patients accepted for heart-lung transplantation, organs became available for 30; 24 patients died waiting, and 13 patients were on the list December 31, 1990. Eight patients died after transplantation. Patients with above-average forced expiratory volume in 1 second (FEV1) (median, 17% predicted) at assessment were half as likely to die waiting (relative risk, 0.47; 95% confidence interval, 0.23 to 0.97) as patients with below-average FEV1. The relative risk of death for patients on the waiting list was 1.44 (95% confidence interval, 1.17 to 1.77) for each increment in PCO2 of 1 kPa. No effect of nutritional status on waiting list death was found, but seven of eight patients who died after heart-lung transplantation were below 80% predicted weight for height. Using a time-dependent analysis, heart-lung transplantation almost halved the risk of death (relative risk, 0.57; 95% confidence interval, 0.22 to 1.48). Postoperative actuarial survival was 79% (95% confidence interval, 63% to 95%).(ABSTRACT TRUNCATED AT 250 WORDS)

The total and differential cell counts of 135 bronchoalveolar lavages (BAL) in 48 heart-lung transplant (HLT) patients were compared with the histologic findings in concurrent transbronchial lung biopsies (TBBs). Counts of CD3+, CD4+, and CD8+ lymphocytes were recorded, and a semiquantitative assessment of HLA-DR and interleukin-2 receptor (IL-2R) expression was made on 29 occasions. There were five diagnostic categories: normal (n = 8), acute rejection (ALR) (n = 57), treated rejection (TR) (n = 19), infection (INF) (n = 24), and chronic rejection (CR) (n = 24). Total cell counts in INF were significantly higher than counts in all the other diagnostic groups. The highest BAL lymphocyte counts, significantly higher than in INF, were found in ALR because of increased CD8+ cells, exceeding 15% in 13 of 57 BALs. TBBs in ALR by contrast showed significantly increased numbers of both CD8+ and CD4+ cells. High dose corticosteroid treatment of ALR caused a fall in cellularity of BAL and TBB specimens but not always to values seen when patients were well. During INF and CR, significantly increased numbers of PMNs were seen in the BAL. HLA-DR and IL-2R expression was enhanced in cells of BAL and TBB in all complications. BAL can only supplement at present histologic examination of TBB in the diagnosis of complications after HLT.

Objective: To compare the pharmacokinetics of cyclosporine in patients with either cystic fibrosis or Eisenmenger's syndrome., Methods: Patients in the study were heart and lung transplant candidates with either cystic fibrosis (n = 6) or Eisenmenger's syndrome (n = 5), as well as patients who received heart and lung transplantation for either cystic fibrosis (n = 13) or Eisenmenger's syndrome (n = 7). This was no experimental pharmacokinetic study in transplant candidates and an exploratory population pharmacokinetic study in transplant recipients., Results: Patients with cystic fibrosis showed higher blood cyclosporine clearance, higher apparent oral clearance, shorter mean residence time, and more erratic absorption. The coefficient of variation of pharmacokinetic parameters was higher in patients with cystic fibrosis. There were no significant differences in metabolite indexes between the two groups of patients after either oral or intravenous administration. A significant negative correlation was found between cyclosporine clearance and hematocrit (r = 0.81 [95% confidence interval, -0.95 to -0.4.1]). Dose-normalized predose blood concentration measurements were lower in patients with cystic fibrosis after transplantation. There was a significant correlation between hematocrit and log dose-normalized cyclosporine concentration (r = 0.40 [95% confidence interval, 0.30 to 0.49]). The total daily dose per 100 ng/ml trough blood concentration required was estimated to be 2.36 times (95% confidence interval, 1.96 to 2.84) higher in patients with cystic fibrosis., Conclusions: Cyclosporine pharmacokinetics is more variable in patients with cystic fibrosis. The difference in cyclosporine clearance between the two groups is accounted for by differences in binding in blood rather than metabolism. The findings suggest that patients with cystic fibrosis could be conservatively given initial oral doses that are 1.5 times higher than those for patients who receive transplants because of Eisenmenger's syndrome.

Since 1987, 21 children under 16 years of age have undergone combined heart and lung transplantation at Great Ormond Street Hospital, London. All children had terminal pulmonary or cardiopulmonary disease. Eight children died one day to 21 months after operation. Actuarial survival was 76% (SEM 10) at 1 year and 60% (SEM 12) at 3 and 4 years after transplantation. 13 children were alive, and all took part in all age-appropriate activities.

1. The relationship between blood cyclosporin concentration (CyACb) and a patient's risk of organ rejection following heart-lung (HL) transplantation was investigated. 2. Longitudinal data were collected for 90 days post-operation for 31 HL transplant recipients. Following exploratory analysis, a multiple logistic regression model with a binary outcome variable representing presence or absence of lung rejection (as defined on biopsy findings and/or intention to treat) in the next 5 days was fitted to the data. 3. A significant interaction between time post-transplant and CyACb was found. During weeks 1-3, the relative risk (RR) of rejection per unit increase in log(e) (5-day mean CyACb) was reduced: RR = 0.29, 95% confidence interval (CI) = (0.12, 0.72). After 3 post-operative weeks, this trend was reversed: RR = 1.61, 95% CI = (0.96, 2.70). Increases in cyclosporin dose (CyAD) and in coefficient of variation (CV) for both CyAD and CyACb over the previous 10 days significantly increased the risk of rejection: RR per unit increase in log(e) (5-day mean CyAD) = 2.72, 95% CI = (1.18, 6.25); RR per increase of 10% (i.e. from, say, 20% to 30%) in the CV for CyAD = 1.20, 95% CI = (1.07, 1.36); RR if the CV for CyACb > 40% = 1.51, 95% CI = (1.01, 2.27). Administration of high dose steroids in the previous 5 days was found to protect against further rejection: RR if steroid treatment was given = 0.23, 95% CI = (0.13, 0.38).(ABSTRACT TRUNCATED AT 250 WORDS)

Seven (11%) of the first 65 patients who received heart transplants at Papworth Hospital were mismatched for Toxoplasma gondii. Of these, four (57%) experienced T. gondii infection and two died. The remaining two had severe symptoms and received anti-T-gondii chemotherapy for a year after transplantation. In an attempt to reduce the impact of donor-acquired T. gondii in our heart transplant recipients, we decided in April 1984 to give prophylactic pyrimethamine to all T. gondii-mismatched patients. In this study, 7 years later, we review the efficacy of this policy. Five of 37 (14%) patients given prophylactic pyrimethamine acquired T. gondii infection; only one was symptomatic, and none died. This compares with 100% symptomatic infection in the pre-1984 patients, who did not receive prophylactic pyrimethamine. We believe that our experience has shown that pyrimethamine is effective in reducing the incidence and severity of primary donor-acquired T. gondii infection in mismatched heart and heart-lung transplant recipients.

The relationship between changes in cyclosporin (CyA) dose or CyA blood concentration and the reciprocal creatinine concentration was investigated by cross-correlation analysis over the first 3 postoperative months in 32 consecutive heart and heart-lung recipients. Exploratory analysis suggested that early changes in renal function, probably attributable to recovery from preoperative cardiac failure, obscured later underlying correlations. Therefore, all data up to the first nadir in plasma creatinine following transplantation were excluded from the analysis. Five-day mean CyA doses or blood concentrations were cross-correlated with 5-day mean reciprocal creatinine concentrations measured either in the same 5-day period or with the creatinine measured up to two 5-day periods later. Although a significant correlation was found between CyA dose and blood concentration (the 95% confidence interval of the population correlation coefficient did not overlap zero), there was no relationship between dose and changes in renal function. The blood CyA concentration, however, correlated significantly with the reciprocal creatinine concentration measured in the same 5-day period and was also predictive of changes in creatinine measured in the subsequent 5-day period. Thus, a major criterion for therapeutic drug monitoring had been fulfilled: CyA dosage adjustment based on blood CyA concentrations, as the intermediate therapeutic end point, is helpful in the management of acute nephrotoxicity in heart and heart-lung transplant recipients because of the lack of a dose-effect relationship. Regular CyA monitoring and appropriate dosage adjustment is essential for the management of acute nephrotoxicity in the first 3 months following heart or heart-lung transplantation.

A decade after the first successful human heart-lung transplantation and with improved recipient survival, there is now a growing interest in the quality of life achieved after this procedure. Patients undergoing heart-lung transplantation suffer from diseases that are most protracted and uniformly fatal. Before surgery, they are usually debilitated from the primary disease and long-term inactivity. Therefore several factors contribute to the maximal work capacity achievable after transplantation. They are principally unavoidable complications of allograft transplantation, mainly lung rejection, but include the toxic effects of immunosuppressant therapy. Many, however, are a function of the prolonged incapacitation and deconditioning imposed by the pretransplant illness. The relative roles of these factors in limiting posttransplant exercise tolerance in the various disease groups undergoing heart-lung transplantation are discussed.

We have examined the diurnal variation in forced expiratory volume in one second (FEV1) in 25 heart-lung transplantation patients over a four week period in order to study the pathophysiological mechanisms underlying the increased mortality and morbidity which occurs at night in asthma. These patients do not have pulmonary autonomic nervous reflexes, but often have muscarinic receptor hypersensitivity. They also develop mixed cell infiltration of the lung tissue in the course of infection or rejection. Thus, they show many features in common with asthma. Seventeen patients (68%) showed a significant diurnal variation in airway calibre (mean amplitude of FEV1 was 4.6% (SD 3.7%)), which is similar to that reported in normal adults. One patient had a diurnal variation of 34.5% during an episode of rejection. This variation fell to 6.9% after steroid therapy, a change often seen in asthma. There was a correlation between increased amplitude of the variation and the presence in transbronchial biopsies of airway submucosal eosinophils and lymphocytes, associated with a histological diagnosis of acute rejection and with epithelial damage. No association was seen with muscarinic receptor sensitivity. The variation in FEV1 showed no alteration from the normal day/night synchronization, and the peak values were around 1300 h. We conclude that the diurnal variation in FEV1 after heart-lung transplantation is not dependent on autonomic nerve reflexes or muscarinic receptor sensitivity, but is related to the consequences of inflammation described above.

As survival improves following heart-lung transplantation (HLT) the importance of obliterative bronchiolitis (OB) as a cause of late death increases. Whilst coronary occlusive disease (COD) may be less common in heart-lung transplant recipients than in patients receiving heart transplants, COD associated with OB can be lethal. We have studied 22 long-term survivors of heart-lung transplantation at an average of 25 months following transplantation during rest and at 50 W supine exercise and with prostacyclin induced vasodilation. Cardiac index increased less with exercise as the physiological measurement of OB using forced expiratory volume in one second (FEV1) fell (P = 0.018). Although resting pulmonary vascular resistance increased with falling FEV1, this increase was still within the normal range. We conclude that a fall in cardiac reserve on exercise accompanies the fall in FEV1 which characterizes OB and may reflect cardiac vascular disease.

Heart-lung and lung transplantation are accepted treatments for patients with end-stage pulmonary vascular disease or parenchymal lung disease. Survival rates for heart-lung and lung transplantation are lower than those for heart transplantation alone. The 5-year actuarial survival for heart-lung transplantation has been 41% largely due to rejection and infection remaining as the limiting factors for long-term survival. A standardized nomenclature for the histological grading of pulmonary rejection was formulated by the International Society for Heart Transplantation (ISHT) in July 1990. Infection, however, is a major problem in the histological assessment of lung recipient biopsies, potentially limiting the usefulness of such a classification. In this study, 100 consecutive transbronchial biopsies (TBBs) from lung transplant recipients were analysed, together with microbiological and serological data, in order to evaluate the proposed ISHT grading system for pulmonary rejection and the importance of concomitant infections in the histological interpretation of TBBs.