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Three hundred-thirteen heart transplant procedures were performed in 303 patients in the 10 years between January 1979 and December 1988. The incidence, histologic type, and site of malignant disease have been analyzed in the 275 patients (91%) who survived more than 1 month after heart transplantation. Four immunosuppressive regimens have been used during this period. Patients 1 through 29 received azathioprine and steroids with 28 days of intravenous antithymocyte globulin. Patients 30 through 89 received cyclosporine and low-dose steroids; the next 61 patients were randomized between cyclosporine and low-dose steroids and cyclosporine and azathioprine; and after patient 150 we have used triple therapy. All cyclosporine-based regimens have included a short course of prophylactic antithymocyte globulin. Eleven malignant tumors have been diagnosed, between 2 months and 6 years after the transplant procedure, and these have been treated by a variety of means. These tumors were two squamous cell carcinomas of the skin; a malignant anal wart that recurred after excision and radiotherapy and necessitated abdominoperineal resection: two small-cell carcinomas of the lung: one squamous cell carcinoma of the esophagus and one of the larynx; two carcinomas of the kidney were found at postmortem examinations; and there were two malignant lymphomas, one of which disseminated rapidly, whereas the other has had prolonged remissions with reduction in immunotherapy with acyclovir. These 11 tumors were responsible for four deaths. No relationship has been demonstrated between type of immunosuppression and tumor development. All patients who are immunosuppressed remain at increased risk for malignant changes. Close surveillance is needed to detect tumors at an early stage.

Sixty patients underwent heart-lung transplantation at our institution between April 1984 and March 1989. The first five donor organs were removed in an adjacent operating room. Subsequently, organs were removed from distant centers. The method of preservation consisted of cold crystalloid cardioplegic arrest of the heart followed by a cold colloid pulmonary artery flush of a perfusate developed at Papworth Hospital. The lung perfusate is preceded by an infusion of prostacyclin into the pulmonary artery, during preliminary dissection of the donor organs. The total ischemic time ranged from 48 to 51 minutes (mean, 49.6 minutes) for the near-procurement group and from 70 to 249 minutes (mean, 157.6 minutes) for the distant-procurement group. Function of the lungs was assessed by gas exchange, pulmonary function tests, extubation, and survival data. Serial x-ray films were used to monitor graft performance in the postoperative period. We record our clinical experience of early graft function after heart-lung transplantation.

Chronic rejection is the major cause of death of long-term survivors of heart-lung transplantation. Of our 61 patients who have received heart-lung transplants, 29 have been followed up for a year or longer. Seven patients had clinical evidence of chronic rejection within 15 months of transplantations of these seven, four died with postmortem confirmation of extensive obliterative bronchiolitis, interstitial and pleural fibrosis, and vascular sclerosis in the heart and lungs. All seven patients had evidence on transbronchial biopsy specimens of submucosal fibrosis and vascular sclerosis. Twelve of our remaining patients have shown similar areas of lung fibrosis on transbronchial biopsy specimens, and the other 10 are well and without fibrosis seen on transbronchial biopsy specimens. Studies of the 201 biopsy specimens obtained from 29 patients confirmed rejection on 130 occasions, with more frequent, more persistent, and more severe rejection in the chronic-rejection group than in the without-fibrosis or lung-fibrosis group. Opportunistic infections resulted in pneumonia on 19 occasions, and these were most commonly found in patients with lung fibrosis. We conclude that chronic lung rejection is the likely outcome in patients with early, poorly controlled, severe rejection.

The histologic changes in transbronchial lung biopsy specimens of heart-lung transplant patients were graded during episodes of acute rejection and when patients were well. Infection was strictly excluded from all episodes studied. Grade of severity of rejection was determined by the magnitude and extent of the inflammatory infiltrate. Biopsy specimens, obtained 1 year after the initial biopsies, were examined for histologic evidence of airway submucosal fibrosis, and each patient's clinical status at this time was recorded. The biopsy material from 22 long-term survivors was studied. On 16 occasions the specimens showed no evidence of rejection (grade 0). Twelve of these sets of specimens were from clinically well patients, and four were from the patients who had clinical evidence of rejection. The other six sets of specimens, from clinically well patients, showed evidence of rejection: three grade 1 and three grade 2. One year later, the clinically well patients had normal biopsy histology without fibrosis and normal lung function. Bronchiolitis obliterans had not developed in any patient. There were 27 episodes of rejection in the 22 patients, of which 23 were confirmed histologically. Eleven sets of specimens had grade 1 acute rejection, eight grade 2, and four grade 3. Three of these patients died, and bronchiolitis obliterans was confirmed at necropsy. Lung fibrosis was more common in specimens taken after 1 year, and lung function was depressed in these patients. The histologic grading of transbronchial lung biopsy material, although still in the early stages of development, provides some predictive value to the long-term outcome of the lung transplant patient, in development of both bronchiolitis obliterans and lesser fibrotic changes.

Triple-drug immunosuppression with cyclosporine, azathioprine, and steroids was introduced at Papworth Hospital in 1986. The management of rejection episodes in the first 40 patients receiving this regimen was reviewed for a minimal follow-up period of 18 months. Routine endomyocardial biopsy specimens were taken and classified into nil, minimal, mild, moderate, and severe rejection categories. Management was dependent on the biopsy result, in addition to the clinical state of the patient. In the early postoperative period (day 0 to 30) 2% of biopsy results showed severe rejection and 27% showed moderate rejection; all but one of the latter patients received augmentation of immunosuppression. In the intermediate period (days 31 to 90) severe rejection was present in 1% and moderate rejection in 36 (31%) of biopsies. Immunosuppression was augmented in 13 symptomatic patients, but in 23 asymptomatic patients additional therapy was withheld and the biopsy was repeated in 5 to 7 days. If moderate rejection was still present (11 cases), immunosuppression was augmented. Later (3 to 12 months) augmentation of immunosuppression was given on only four occasions. When the histologic criteria for diagnosis of moderate rejection are present during the early period after transplantation, we recommend augmented immunosuppression. In cases of later rejection we suggest that the decision be based on the biopsy result and the clinical condition of the patient; however, a prospective controlled trial will be required to confirm that this policy is correct.

Peripheral T-cell subsets were monitored in ten heart and two heart-lung recipients pre- and up to one year post-operatively. Prior to transplantation four patients had T-helper/T-cytotoxic suppressor ratios (TH/TS-C) above the range for normal healthy controls and all required treatment for rejection episodes, as compared with three of eight patients whose pre-transplantation ratios were within the normal range. No patient with high TH/TS-C ratios developed cytomegalovirus infection as compared with all of the eight patients with normal ratios. Post-transplantation cytomegalovirus infection was the major cause of alterations in TH/TS-C ratios. T-cell subset inversion always preceded the diagnostic rise in cytomegalovirus antibody titre in both primary and secondary cytomegalovirus infections. Inversion was also noted with Pneumocystis carinii infection. Reversal of the TH/TS-C ratio was due to a major increase in the absolute numbers of TS-C cells and was usually followed by a rise in the number of cells expressing a natural killer cell phenotypic marker (Leu-7). All patients with primary cytomegalovirus and two of four cases with secondary cytomegalovirus retained inversion throughout follow-up and showed significantly increased numbers of TS-C and Leu-7 bearing cells. However, the absolute numbers of TH fell by 200 days after transplantation in all patients irrespective of their TH/TS-C ratio. Although TH/TS-C ratio inversion was a predictor of cytomegalovirus infection, no association was found between changes in T-cell subsets after transplantation and rejection episodes.

A system that uses a chemical method of cooling has been developed for the storage and transport of heart and heart-lung donor organs. This provides a precisely controlled environmental temperature without the use of ice, with its attendant problems of availability and potential contamination with pathogens. Storage and preservation solutions are transported to the donor hospital within the temperature-controlled polyurethane container, and the organs are returned in the same container, within an inflatable cushion. We have used this method for the distant procurement of over 260 hearts and for the most recent 30 heart-lung organ blocks. The mean ischemic time for hearts is 2.5 hours (1.5 to 4.2 hours) and for heart-lung blocks 2.2 hours (1.2 to 4.1 hours). Most donors give multiple organs such as kidney, liver, and pancreas. One patient received heart and kidney grafts from the same donor, and another received combined heart-lung and liver grafts. In relation to primary donor organ failure, there have been four deaths of patients who have had heart transplantations and no deaths of patients who received heart-lung organ blocks. We believe that the method offers advantages over the more conventional methods of organ storage with regard to convenience, temperature control, and sterility.

Between April 1984 and August 1987, 27 patients have received heart-lung transplantations at Papworth Hospital. In the first 17 patients endomyocardial biopsies were performed routinely in accordance with the practice for heart transplant recipients. It became apparent that in contrast to heart transplant recipients, heart-lung transplant recipients show little evidence of cardiac rejection. As routine endomyocardial biopsies did not contribute therefore to patient management, they were stopped. Conversely, pulmonary rejection was diagnosed either clinically by a decrease in forced expired volume in 1 second (FEV1) in the absence of lung infection or by transbronchial biopsy, which determined when immunosuppression needed to be augmented. The presence of lung rejection was confirmed by resolution of the lung histopathology or improvement in FEV1.

In our experience a lung biopsy specimen taken by means of a fiberoptic bronchoscope is a useful, safe technique for the diagnosis of rejection in heart-lung transplant recipients. To determine that the histologic features associated with rejection can be identified in transbronchial biopsy specimens, 35 biopsy specimens (group A) taken when retrospective review confirmed a clinical diagnosis of rejection without evidence of infection were identified from a total of 107 biopsy specimens. These were compared with 14 biopsy specimens (group B) taken when the patients were well. Several foci of dense perivascular mononuclear cell infiltration with pyroninophilic lymphocytes and plasma cells were seen in 79% of group A biopsy specimens. Fewer foci of non-pyroninophilic cells were seen in group B biopsy specimens (p = 0.005). There was also a difference in the histologic features of the mucosa and interstitial lung tissue. We believe that the early confirmation of rejection followed by adequate augmentation of immunosuppression may prove to be an important factor in reducing the incidence of obliterative bronchiolitis in heart-lung transplant recipients.

A fatal early acute rejection occurred in a heart allograft recipient immunosuppressed with Cyclosporine. This failure to prevent rejection in spite of satisfactory plasma levels of Cyclosporine was associated with total absence of renal impairment. The latter has always been present in our experience. The absence of immune and nephrotoxic effects raises the question of a biological defect in this patient, possibly a lack of specific receptors for Cyclosporine.

Infectious complications constitute a major cause of morbidity and mortality after heart transplantation. Those infections transmitted with the transplanted heart are potentially avoidable. Cytomegalovirus infections and toxoplasmosis occupy a prominent position in this category. The outcome of transplanting hearts from donors previously exposed to these infections depends largely on the existing immune status of the recipient. This paper is a retrospective study on the incidence of Toxoplasma gondii and cytomegalovirus infections in patients undergoing heart and heart-lung transplantation at Papworth Hospital, Cambridge.