Cystic fibrosis liver disease: to transplant or not to transplant?

Biliary cirrhosis complicates some adults with cystic fibrosis (CF) and may require transplantation. Cardio-respiratory disease severity varies such that patients may require liver transplantation, heart/lung/liver (triple) grafts or may be too ill for any procedure. A 15-year experience of adults with CF-related liver disease referred for liver transplantation is presented with patient survival as outcome. Twelve patients were listed for triple grafting. Four died of respiratory disease after prolonged waits (4-171 weeks). Eight underwent transplantation (median wait 62 weeks); 5-year actuarial survival was 37.5%. Four died perioperatively; only one is alive at 8-years. Eighteen patients underwent liver transplant alone (median wait 7 weeks); 1- and 5-year actuarial survival rates were 100% and 69%. Three long-term survivors required further organ replacement (two heart/lung and one renal). Two others were turned down for heart/lung transplantation and four have significant renal impairment. Results for triple grafting were poor with unacceptable waiting times. Results for liver transplant alone were satisfactory, with acceptable waiting times and survival. However, further grafts were required and renal impairment was frequent. The policy of early liver transplantation for adults with CF with a view to subsequent heart/lung or renal transplantation needs assessment in the context of long-term outcome.

Myocardial localization and isoforms of neural cell adhesion molecule (N-CAM) in the developing and transplanted human heart.

Neural cell adhesion molecule (N-CAM) has been implicated in cellular interactions involved in cardiac morphogenesis and innervation. Immunohistochemical techniques and Western blot analysis were used to determine the localization and isoforms of N-CAM in the developing and extrinsically denervated human heart. Myocardial and conducting cells in the fetal heart (7-24 wk gestation) exhibited sarcolemmal immunoreactivity, the major desialo N-CAM isoforms being 150, 145, 120, 115, and 110 kD. N-CAM expression appeared to be downregulated in the myocardium during adult life, with relatively little sarcolemmal immunoreactivity being detected in normal donor tissues. In contrast to the temporal changes observed in the myocardium, both the developing and mature cardiac innervation displayed N-CAM immunofluorescence staining, localized to neuronal cell bodies, nerve fascicles and fibres. Extrinsically denervated cardiac allografts, obtained 2 d to 91 mo after transplantation, showed extensive sarcolemmal and intercalated disc immunostaining and expression of 125-, 120-, and 115-kD isoforms. Tissues from explanted recipient hearts and atrial appendage samples obtained during coronary bypass graft operations were also examined and displayed varying amounts of N-CAM immunoreactivity. We conclude that the expression of N-CAM immunoreactivity and isoforms in the human heart is developmentally regulated and may be modulated by factors such as cardiac innervation and myocardial hypertrophy.

Extended ganciclovir prophylaxis in lung transplantation.

BACKGROUND: Positive cytomegaloviral status of the donor or of the recipient adversely affects survival and enhances the development of bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. The role of ganciclovir prophylaxis in cytomegalovirus infection in respect to obliterative bronchiolitis or to BOS development is not known. METHODS: From the Papworth transplant database, we identified 146 patients who received organs from cytomegalovirus-positive donors. We classified patients into 3 groups as follows: Group 1 consisted of 42 patients who underwent transplantation between 1990 and 1992 when no prophylaxis was given; Group 2 consisted of 49 patients who underwent transplantation between 1992 and 1995 when 4 weeks of IV ganciclovir was given as prophylaxis; and Group 3 consisted of 55 patients who underwent transplantation between 1995 and 1998 when cytomegalovirus prophylaxis consisted of IV (1 week) followed by oral ganciclovir for a total of 3 months. Donor management, recipient management during and after surgery, and pharmacotherapy were uniform during the study period. We used survival and regression methods to compare these groups, adjusting for the transplantation type (single lung, double lung, or heart-lung) and for HLA typing. RESULTS: We found a significant difference among all 3 groups in numbers of cytomegaloviral disease episodes in the 1st year after transplantation. The number of rejection episodes in the 3 groups during the 1st post-transplant year gradually decreased from Group 1 to Group 3. We identified no statistically significant benefit in the time to BOS occurrence or in actuarial survival. CONCLUSION: Extended prophylaxis with IV and oral ganciclovir practically abolishes cytomegaloviral disease and is related to a decreased incidence of rejection episodes. However, ganciclovir prophylaxis is not related to a decreased incidence or progression of BOS or survival.

Aortic valve replacement for late infective endocarditis after heart-lung transplantation.

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.

Pharmacokinetics of cyclosporine in heart and lung transplant candidates and recipients with cystic fibrosis and Eisenmenger's syndrome.

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.

Heart-lung transplantation: better use of resources.

PURPOSE: Our goal was to review the experience at Papworth Hospital, Cambridgeshire, England, with combined heart-lung transplantation. PATIENTS AND METHODS: Since April 1984, 31 patients have undergone heart-lung transplantation. Donors and recipients are carefully matched with regards to serology, morphology, and cytomegalovirus compatibility. A pulmonary preservation fluid has been developed that allows distant organ procurement with a single pulmonary artery flush technique. RESULTS: Acute cardiac rejection has not occurred in these patients. Twenty-three patients are alive between two months and over three years following transplantation. The actuarial survival rate at one year is 78 percent, and 70 percent at two years. Three patients died as a result of cytomegalovirus pneumonitis; in two patients, obliterative bronchiolitis developed, and both died, one after an opportunistic infection developed. Three patients died from other causes. The use of transbronchial biopsy of the lung has provided accurate, early, and safe diagnosis of pulmonary rejection. CONCLUSION: Developments in organ preservation and patient management, as well as careful selection of recipients and donors, have led to the effective use of resources and thereby to these good results. In particular, the incidence of obliterative bronchiolitis has been low, which is attributed to the early treatment of pulmonary rejection following diagnosis by transbronchial biopsy.

Transbronchial lung biopsy for the diagnosis of rejection in heart-lung transplant patients.

Long-term success of human lung transplantation has been hindered by the lack of an effective and repeatable method of obtained tissue from the transplanted lung for histology. Management of patients is complicated by the difficulty in distinguishing clinically between opportunistic infection of the lung and rejection. As a result, a large number of patients in recent reports develop chronic disabling obliterative bronchiolitis, believed to be the consequence of "chronic" rejection. Twenty-one patients have undergone heart-lung transplantation in our institute since 1984. During fiberoptic bronchoscopy, 43 transbronchial lung biopsies were performed in 15 patients. Twenty episodes of rejection occurred in 11 patients, from whom 16 sets of biopsies showed the typical changes of perivascular infiltrate and mucosal inflammation. Three biopsies were falsely negative; six routine biopsies performed when patients were well were all normal. Overall sensitivity was 84% and specificity 100%. By contrast, the sensitivity of the chest radiograph was only 40%. Opportunistic lung infection in 8 patients was diagnosed by transbronchial biopsy with a sensitivity of 38% and specificity of 100%. In no patient with opportunistic infection were the histologic features of rejection seen. Transbronchial lung biopsy offers a safe and repeatable method to obtain tissue from heart-lung transplants for histology. It has enabled the management of the lung transplant patient to be equivalent to that of the kidney, liver, and heart transplant patient.

Distant procurement of organs for clinical heart-lung transplantation using a single flush technique.

A more widespread application of combined heart-lung transplantation (HLT) for the treatment of pulmonary vascular disease has been limited by the lack of a simple and inexpensive method for preserving donor organs for transplantation from distant hospitals. Of the 12 HLT patients treated at Papworth Hospital, the last 7 involved distant procurement of donor organs. For this, a single flush hypothermic system was used, with a Ringer's solution containing albumin, mannitol, prostacyclin, and heparin. This was preceded by a prostacyclin infusion into the donor's pulmonary artery. A retrospective comparison has been made of the post-operative pulmonary function between the HLT patients with distant procurement, those with near procurement of organs, and a group of patients who underwent coronary artery bypass graft (CABG) over the same time span. The mean ischemic time for distant-procurement patients was 110 (+/- 10) min, compared with 50 (+/- 0.5) min for near procurement. During the initial 18 hr postoperatively, the alveolar-arterial oxygen gradients (A-aDO2) for both groups of HLT patients and the CABG patients were closely comparable. Two near-procurement patients died: 1 from tracheal dehiscence, and 1 from cytomegalovirus (CMV). One distant-procurement patient died of CMV. All the others recovered fully and are alive and well at home. No patient developed a classical reimplantation response, and pulmonary function in the distant-procurement group compared closely with the CABG patients. These observations suggest that a simple single flush preservation system can effectively extend the pulmonary ischemic time so facilitating distant organ procurement.

Metabolic changes in the autotransplanted baboon heart.

Chronic denervation of the heart leads to depletion of tissue catecholamines, giving rise to metabolic abnormalities, including a reduction in cardiac glucose oxidation. Impaired glucose oxidation could cause an increased oxidation of fat, which in turn could lead to development of coronary artery disease. Cardiac glucose oxidation (using 14C-(U),D-glucose) was studied in female baboons, before, and three to five weeks after, autotransplantation. Systemic arterial and coronary sinus samples were analyzed for total CO2 content, O2 content, 14CO2, glucose, lactate, pH, PCO2, and PO2. Tissue for metabolite assays (adenosine-5'-triphosphate [ADP] and creatine phosphate [CP]; glucose-6-phosphate [G6P] and fructose 6-phosphate [F6P] was obtained from the right ventricle before and after autotransplantation in some animals. There were no significant changes. Tissue was also obtained postmortem for analysis of noradrenaline, soluble tyrosine hydroxylase activity, and contractile and regulatory proteins. There was a large decrease in tissue noradrenaline, suggesting almost total sympathetic denervation. The level of tyrosine hydroxylase activity shows that the denervated heart can synthesize dopamine. There were no detectable changes in the contractile or regulatory proteins. In six of the nine baboons successfully studied, there was a distinct decrease in the oxidation of glucose after autotransplantation (P less than 0.05). This indicates that the removal of the sympathetic and parasympathetic nerve supply to the heart affects the ratio of glucose oxidized to other substrates.

Evidence that long-term survival of concordant xenografts is achieved by inhibition of antispecies antibody production.

Antibody and complement have been shown to be of primary importance in the rejection of hamster heart xenografts by rats. Very high anti-hamster antibody titers were detected at the time of rejection of hamster hearts transplanted into untreated or T cell deficient rats. This study demonstrates a method of inhibiting this antibody production by pulse therapy with cyclophosphamide (CyP) and continuous cyclosporine treatment, resulting in a median survival of the hamster heart of greater than 100 days. Controls and CsA-treated rats reject the transplanted hamster heart in a median of 3 days. CyP as a sole therapy resulted in a median survival of 14 days. Prolonged CyP therapy when combined with CsA was associated with increased death among rat recipients due to infection. Antispecies antibody production was suppressed during CyP and CsA therapy and did not recur after cessation of CyP therapy. Cessation of CsA therapy at 60 and 100 days posttransplantation resulted in subsequent rejection of the xenografts (median survival after cessation of therapy of 11 and 19.5 days, respectively) and was associated with production of rat anti-hamster antibodies.

Pharmacodynamics of cyclosporine in heart and heart-lung transplant recipients. I: Blood cyclosporine concentrations and other risk factors for cardiac allograft rejection.

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.

Pharmacodynamics of cyclosporine in heart and heart-lung transplant recipients. II: Blood cyclosporine concentrations and other risk factors for lung allograft rejection.

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.

The effect of recipient lung size on lung physiology after heart-lung transplantation.

We studied the postoperative course of lung volumes in 32 heart-lung transplant recipients relative to the predicted total lung capacity of the individual donors, to assess the degree of inaccuracy likely to result from the radiological method of matching of donor and recipient lung sizes. There was a tendency for recipients with large preoperative lung volumes--from, for example, emphysema--to receive smaller lungs, while those with smaller volumes from pulmonary vascular disease received bigger donor lungs, but no immediate problems were incurred. After an initial fall in total lung capacity, the postoperative value of the total lung capacity approached the recipients' pretransplant value about one year after the operation irrespective of the size of the donor lungs. This suggests that chest wall compliance is the major determinant of postoperative lung volume and not the donor lung size or compliance. Exact matching of donors' and recipients' lung sizes may not be necessary, and if required can be simply achieved by comparing the measured total lung capacity in the recipient with the predicted value of the donor based on sex, age, and height.

Development of bronchiolitis obliterans syndrome in recipients of heart-lung transplantation--early risk factors.

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.

Randomized trial of blood eosinophil count monitoring as a guide to corticosteroid dosage adjustment after heart transplantation.

BACKGROUND: Increases in blood eosinophil counts (EOS) beyond 0.06 x 10(9)/liter precede treated heart allograft rejection. An oral prednisolone dose of 0.35 mg/kg/day usually suppresses EOS below this threshold. METHODS: We designed a randomized trial to compare our empirical protocol for steroid dose adjustment with a novel protocol guided by EOS monitoring during the first 3 months after heart transplantation. Eighty patients were randomized to either have their EOS reported and used for steroid dose adjustment (RG; n=40), or not reported (NG; n=40). RG patients had their steroid dosage increased if EOS exceeded 0.06 x 10(9)/liter. RESULTS: RG patients had an 83% lower risk of treated rejection (P=0.035) and lower median intravenous dose of methyl-prednisolone (P=0.017) than NG during the first 6 postoperative weeks. The proportion of diagnostic increases in EOS that were followed within 2 weeks by treated rejection was 42% greater in NG than RG (P=0.0001), compatible with a direct impact of EOS-guided prednisolone dose adjustment on the risk of subsequent rejection. Overall, RG had less than half the risk of rejection of any grade (P<0.001) and significantly more rejection-free biopsies than NG (P=0.001). The mean oral prednisolone dosage was significantly greater in RG than NG during the first (P=0.014) and second (P=0.001) 6 weeks of follow-up. This did not increase the incidence of serious steroid-related side effects. CONCLUSIONS: EOS monitoring is a simple, cheap, and effective means of optimizing steroid immunosuppression. Restriction of the EOS-guided steroid dosing protocol to periods of prolonged hospitalisation during the first 3 postoperative months should limit the requirement for higher prednisolone dosage without affecting immunosuppressive efficacy.

Herpes simplex virus infection in heart-lung transplant recipients.

We report our experience of herpes simplex virus infection in a series of 51 recipients of heart lung transplantation (HLT). Nine patients, all of whom were seropositive for the virus preoperatively, developed HSV infection. Seven episodes of culture-proved mucocutaneous HSV infection without evidence of pulmonary involvement occurred in four patients. Six episodes of HSV pneumonia were seen in a further five patients, one of whom died. Diagnosis of HSV pneumonia was by histological appearances on transbronchial biopsy, together with culture of lung tissue or bronchoalveolar lavage. Concomitant cytomegalovirus infection occurred in four patients. All patients who developed HSV pneumonia did so within the first two postoperative months; in four patients following augmented immunosuppression. We now suggest that HLT recipients who are HSV antibody-positive should receive prophylactic acyclovir for the first two months after surgery and at times of augmented immunosuppression.

Infection and reactivation with cytomegalovirus strains in lung transplant recipients.

Cytomegalovirus pneumonia is a major cause of morbidity and death following lung transplantation (LT) (1). The case fatality rate is highest in the CMV-seronegative recipients (R-) of organs from seropositive donors (D+), which suggests that transmission of CMV may occur with the graft (1), but in seropositive recipients (R+) the comparative importance of reactivation of endogenous virus and reinfection with donor virus is poorly understood.

Risk factor analysis for the major hazards following heart transplantation--rejection, infection, and coronary occlusive disease.

This study demonstrates the importance of analyzing survival by cause of death in order to achieve a better understanding of the prognostic indicators involved. It further emphasizes the need for analysis of risk factors in both univariate and multivariate models, and the danger of making judgements based on premature analysis of data on follow-up after heart transplantation. Survival following transplantation is characterized by the major hazards of early death due to infection and rejection and late graft loss due to coronary occlusive disease (COD). This study summarizes the first-graft survival experience for 323 transplant patients at Papworth Hospital, and assesses a number of potential risk factors for (1) early mortality, (2) late mortality from COD, and (3) development of COD. The potential risk factors considered for all hazards are donor and recipient age, sex, blood group, and matching of these factors; donor cause of death and recipient immunosuppression; inotropic support; waiting time; preoperative diagnosis and previous cardiac surgery; ischemic time; and extubation time. In addition, for development of, and graft loss from, COD, perioperative rejection and cytomegalovirus infection; hypertension at discharge; and cholesterol, triglycerides, and lipids at two years were assessed as risk factors. Advances in immunosuppression were observed to have increased overall survival rates and decreased mortality from infection, rejection, and COD, as well as decreasing morbidity from COD. Fatal rejection was found to be more likely in female recipients, recipients over 40 years, recipients of grafts from donors over 30 years old, patients who were transplanted for valvular heart disease, and patients who waited less than three months for their transplant. Male recipients of female donor organs were more likely to lose their grafts as a result of COD. Patients older than 50 and hearts from donors older than 40 conferred a high risk of development of and loss from COD. Patients transplanted for ischemic heart disease were more likely to develop COD. High cholesterol, low HDL, high LDL, and high triglycerides at two years after transplant showed some evidence of high risk for the subsequent development of COD, although these relationships are not statistically significant at this stage. Contrary to other recent studies, cytomegalovirus infection was not found to be a risk factor for the development of COD.

Hyperacute lung rejection in a pig-to-human transplant model: the role of anti-pig antibody and complement.

BACKGROUND: The physiology of hyperacute rejection of pig lung by human blood and the role of antispecies antibody and complement in this phenomenon have not previously been characterized. METHODS: Human blood was perfused through an ex vivo pig heart-lung preparation. In the treatment groups, blood was either unmodified or modified to deplete alternative pathway complement (heat treatment), anti-pig antibody, or both. Control experiments were performed with unmodified and heat-treated pig blood. Physiologic parameters, organ survival, and immunohistology were the primary outcome measures assessed. RESULTS: Pig lung was consistently damaged by human blood within 45 min (median 20 min), as evidenced by elevated pulmonary vascular resistance and parenchymal injury. Immunohistologic studies of perfused lungs showed prominent deposition of IgM and classical pathway component, C4, and weaker deposition of alternative pathway component, properdin. Heat treatment did not impede the rise in pulmonary vascular resistance or significantly prolong survival. Depletion of anti-pig antibody prolonged survival (median 90 min) and attenuated the rise in pulmonary vascular resistance. Antibody absorption, combined with heat treatment of plasma, prevented the elevation in pulmonary vascular resistance and yielded median graft survival (210 min) similar to pig blood perfusion (approximately 240 min). CONCLUSIONS: These results show that elevated pulmonary vascular resistance and pulmonary parenchymal injury are mediated at least in part by antispecies antibody and heat-sensitive pathways. They are consistent with the hypothesis that complement activation contributes significantly to acute lung damage in the pig-to-human species combination.

Blood cyclosporine concentrations and cytomegalovirus infection following heart transplantation.

We have attempted to identify major risk factors for cytomegalovirus (CMV) infection and disease following heart transplantation, with emphasis on the degree and type of immunosuppression used. One hundred and eleven consecutive heart transplant recipients were studied for the first 4 months. Data from the 95 who survived at least 1 month were analyzed using multiple Cox regression. Blood cyclosporine concentrations (CsAbc) > 550 micrograms L-1 were associated with a 4.4-fold increase in risk of CMV infection during the next week (95% confidence interval = 1.2-16.2). Other significant risk factors for CMV infection included antirejection treatment in the past 14 days, a drop in white blood cell count, receiving a CMV antibody-positive donor organ, and primary diagnosis other than cardiomyopathy. We found that patients experiencing a CMV infection were at 3 times the risk of subsequently developing symptomatic CMV disease (95% confidence interval = 1.1-9.7). In addition, the proportion of patients developing symptomatic CMV disease was significantly higher amongst those with a median CsAbc > 550 micrograms L-1 for at least 1 week (29% vs. 10%; P = 0.02) or who had been treated for rejection more frequently than once every 6 weeks (31% vs. 12%; P = 0.04) during the first 4 months. CMV antibody-negative recipients of antibody-positive donor organs had a higher rate of symptomatic CMV disease than did other serological combinations (67% vs. 10%; P = 0.0001). We conclude that the risk of CMV infection and symptomatic disease following heart transplantation may be critically influenced by early management of immunosuppression as well as by donor serology.