Heart-lung Transplant Recipients Research Articles

Pneumocystis Pneumonia in Solid Organ Transplant Recipients

Pneumocystis spp. are thought to be ubiquitous in nature with serologic studies suggesting that exposure occurs commonly in childhood (2). Symptomatic Pneumocystis pneumonia (PCP) is generally limited to individuals with immune deficits. Animal models demonstrate both de novo infection via airborne transmission and by reactivation of previously established latent infections (3). Clusters of infection have been described in medical facilities among renal transplant recipients (4–6). Based on studies before routine implementation of prophylaxis, the overall incidence of infection among solid organ transplant recipients varied mostly in the range of 5–15% depending on organ type, transplant center and immunosuppressive regimens (7). In older reports before implementation of extensive prophylaxis, the attack rate appeared highest in lung and combined heart–lung transplant recipients with an overall incidence ranging from less than 10% to just over 40%. Among liver and kidney transplant recipients, the incidence appeared to be less at anywhere from close to 2% to 10–15% (1). The incidence overall may be decreasing with reduction in the routine use of corticosteroids in organ transplantation and the adoption of effective prophylactic measures. Table 1 outlines some risk factors for PCP among non-HIV-infected individuals.

A prospective, randomized, crossover pilot study of inhaled nitric oxide versus inhaled prostacyclin in heart transplant and lung transplant recipients

Inhaled nitric oxide has been shown to reduce pulmonary vascular resistance in patients undergoing cardiothoracic surgery, but it is limited by toxicity, the need for special monitoring, and cost. Inhaled prostacyclin also decreases pulmonary artery pressure, is relatively free of toxicity, requires no specific monitoring, and is less expensive. The objective of this study was to compare nitric oxide and prostacyclin in the treatment of pulmonary hypertension, refractory hypoxemia, and right ventricular dysfunction in thoracic transplant recipients in a prospective, randomized, crossover pilot trial. Heart transplant and lung transplant recipients were randomized to nitric oxide or prostacyclin as initial treatment, followed by a crossover to the other agent after 6 hours. Pulmonary vasodilators were initiated in the operating room for pulmonary hypertension, refractory hypoxemia, or right ventricular dysfunction. Nitric oxide was administered at 20 ppm, and prostacyclin was administered at 20,000 ng/mL. Hemodynamic and oxygenation parameters were recorded before and after initiation of pulmonary vasodilator therapy. At 6 hours, the hemodynamic and oxygenation parameters were recorded again, just before discontinuing the initial agent. Crossover baseline parameters were measured 30 minutes after the initial agent had been stopped. The crossover agent was then started, and the hemodynamic and oxygenation parameters were measured again 30 minutes later. Heart transplant and lung transplant recipients (n = 25) were randomized by initial treatment (nitric oxide, n = 14; prostacyclin, n = 11). Nitric oxide and prostacyclin both reduced pulmonary artery pressure and central venous pressure, and improved cardiac index and mixed venous oxygen saturation on initiation of therapy. More importantly, at the 6-hour crossover trial, there were no significant differences between nitric oxide and prostacyclin in the reduction of pulmonary artery pressures or central venous pressure, or in improvement in cardiac index or mixed venous oxygen saturation. Nitric oxide and prostacyclin did not affect the oxygenation index or systemic blood pressure. There were no complications associated with nitric oxide or prostacyclin. In heart transplant and lung transplant recipients, nitric oxide and prostacyclin similarly reduce pulmonary artery pressures and central venous pressure, and improve cardiac index and mixed venous oxygen saturation. Inhaled prostacyclin may offer an alternative to nitric oxide in the treatment of pulmonary hypertension in thoracic transplantation.

A multi-drug regimen for respiratory syncytial virus and parainfluenza virus infections in adult lung and heart-lung transplant recipients

Respiratory syncytial virus (RSV) and parainfluenza virus (PIV) can cause significant morbidity and mortality in lung and heart-lung transplant recipients. We evaluated the utility of a multi-drug protocol for the treatment of RSV- and PIV-related infections. RSV or PIV was identified in 25 patients with a total of 29 infectious episodes between January 2006 and December 2007. The study included 20 women and 5 men, mean age 42 +/- 13 years. Fifteen patients had received bilateral lung transplant and the remainder either received single lung or heart-lung transplant. Mean time from transplant to infection was 1192 days. RSV was identified in 23 cases, PIV in 7 cases. Patients underwent treatment with inhaled ribavirin, methylprednisolone, and intravenous immunoglobulin (IVIG). RSV-positive patients were also treated with palivizumab. We retrospectively evaluated their clinical status and pulmonary function for a 1-year interval before and after the date of infection. Average baseline forced expiratory volume in 1 s (FEV(1)) before infection was 2.14 +/- 0.68 L/min. Average decline in FEV(1) was 5.7% at the time of infection. Average FEV(1) during post-treatment follow-up was not significantly different than baseline (2.16 +/- 0.80 L/min). Among patients with bronchiolitis obliterans syndrome (BOS) stages 1, 2, or 3 at the time of infection, average FEV(1) declined by 14.8% and remained lower at 9.1% during follow-up when compared with patients with BOS stages 0 or 0p. No complications resulted from treatment. One patient died during follow-up as a result of pre-existing liver failure. This study of lung and heart-lung transplant recipients infected with RSV and PIV shows that a multi-drug regimen including inhaled ribavirin, corticosteroids, and IVIG (with or without palivizumab) is safe and effective. Prompt diagnosis and therapy for patients with RSV or PIV infections are critical for maintaining lung function.

Trends in invasive disease due to Candida species following heart and lung transplantation

Although invasive candidiasis (IC) causes significant morbidity and mortality in patients who undergo heart, lung, or heart-lung transplantation, a systematic study in a large cohort of thoracic organ transplant recipients has not been reported to date. Clinical and microbiological data were reviewed for 1305 patients who underwent thoracic organ transplantation at Stanford University Medical Center between 1980 and 2004. We identified and analyzed 76 episodes of IC in 68 patients (overall incidence 5.2% per patient).The incidence of IC was higher in lung (LTx) and heart-lung transplant (HLTx) recipients as compared with heart transplant (HTx) recipients (risk ratio [RR] 1.7, 95% confidence interval [CI] 1.1-2.7).The incidence of IC decreased over time in all thoracic organ transplant recipients, decreasing from 6.1% in the 1980-1986 time period to 2.1% in the 2001-2004 era in the HTx recipients, and from 20% in the 1980-1986 period to 1.8% in the 2001-2004 period in the LTx and HLTx recipients.The most common site of infection differed between the HTx and LTx cohorts, with bloodstream or disseminated disease in the former and tracheobronchitis in the latter. IC in the first year after transplant was significantly associated with death in both HTx (RR 2.9, 95% CI 1.8-4.6, P=0.001) and LTx and HLTx patients (RR 3.0, 95% CI 1.9-4.6, P<0.001). The attributable mortality from IC decreased during the 25-year period of observation, from 36% to 20% in the HTx recipients and from 39% to 15% in the LTx and HLTx recipients. There were a significant number of cases caused by non-albicans Candida species in all patients, with a trend toward higher mortality in the HTx group. In conclusion, the incidence and attributable mortality of IC in thoracic organ transplant recipients has significantly declined over the past 25 years.The use of newer antifungal agents for prophylaxis and treatment, the decrease in the incidence of cytomegalovirus disease, and the use of more selective immunosuppression, among other factors, may have been responsible for this change.

Detection of Epstein–Barr virus DNA in peripheral blood is associated with the development of bronchiolitis obliterans syndrome after lung transplantation

Background The long-term success of lung transplantation is limited by the development of bronchiolitis obliterans syndrome (BOS). Virus infections may be involved in the development of BOS. Objectives The study intended to investigate whether there is an association of Epstein–Barr virus (EBV), cytomegalovirus (CMV) and human adenovirus (HAdV) with the development of BOS and to identify risk factors for EBV detection in blood. Study design A prospective cohort study was conducted in lung and heart–lung transplant recipients (LTR) who are followed in our outpatient clinic. 385 LTR were monitored for CMV pp65 antigen, EBV and HAdV DNA in blood at follow-up visits for 6 months. The development of BOS was recorded for a median of 21 months. Results EBV DNA, HAdV DNA and CMV pp65 antigen were detected at least once in, respectively, 202/385 LTR (52.5%), 10/382 LTR (2.6%) and 19/385 LTR (4.9%). Repeated EBV DNA detection and acute rejection were associated with the development of BOS. Variables associated with EBV DNA detection in blood were the diagnosis of BOS before study entry, retransplantation and immunosuppressive therapy with sirolimus or everolimus. Conclusions EBV reactivation is frequent in LTR. The variables found associated with EBV reactivation probably reflect increased immunosuppression. Repeated EBV DNA detection in blood, possibly reflecting chronic EBV replication, is associated with the development of BOS. The elucidation of whether and how EBV DNAemia triggers the development of BOS could improve long-term survival of LTR.

682: 1-Year Results of the First 120 Patients Enrolled in a 3-Year Randomised, Open Label, Multi-Centre Investigator Driven Study Comparing De Novo Enteric Coated Mycophenolate Sodium with Delayed Onset Everolimus, Both Arms in Combination with Cyclosporin (Using C2 Monitoring) and Corticosteroids for the Prevention of Bronchiolitis Obliterans Syndrome in Heart-Lung, Bilateral Lung and Single Lung Transplant Recipients

682: 1-Year Results of the First 120 Patients Enrolled in a 3-Year Randomised, Open Label, Multi-Centre Investigator Driven Study Comparing De Novo Enteric Coated Mycophenolate Sodium with Delayed Onset Everolimus, Both Arms in Combination with Cyclosporin (Using C2 Monitoring) and Corticosteroids for the Prevention of Bronchiolitis Obliterans Syndrome in Heart-Lung, Bilateral Lung and Single Lung Transplant Recipients

Human Herpesvirus-8 Serology in Pediatric Organ Transplantation

Human herpesvirus (HHV)-8 has been demonstrated to be involved in the pathogenesis of Kaposi's sarcoma, body cavity lymphomas, multicentric Castleman disease, and, more recently, acute bone marrow failure. In order to study the correlation between HHV-8 and immunosuppression, we performed a serological study in a group of 28 pediatric heart and heart-lung transplant recipients; of mean age 11.5 ± 2.5 years. We analyzed blood samples prior to, at 3 to 6 months, and at least 12 months after transplantation. All patients were negative pretransplantation. We observed 10 seroconversions: one patient at 6 months; two patients at 12 months; and seven within the third year after transplantation. Our preliminary data demonstrated that HHV-8 seroconversion is frequent among pediatric transplant recipients. It was probably related to the length of immunosuppression rather than the organ transplantation; Serological assays of all donor specimens of seroconverted patients were negative.

Long-Term Outcome of Lung and Heart-Lung Transplantation for Idiopathic Pulmonary Arterial Hypertension

The survival after lung and heart-lung transplantation for idiopathic pulmonary arterial hypertension has been reportedly the lowest among the major diagnostic categories of lung transplant recipients. Retrospective analysis was performed for lung and heart-lung transplant recipients for idiopathic pulmonary arterial hypertension from 1982 to 2006. The patients were divided into 2 groups, based on the era; group 1: 1982 to 1993, and group 2: 1994 to 2006. Since 1994, we have introduced our current protocols including prostaglandin E1 and nitroglycerin for donor lung preservation, and lung protection with cold and terminal warm blood pneumoplegia as well as immunosuppression with alemtuzumab induction. These modifications were introduced in different years over a wide span of time (1994 to 2003). Group 1 had 59 patients (35 +/- 1 years old, ranging 15 to 53, 20 male and 39 female) with 7 single lung, 11 double lung, and 41 heart-lung, whereas group 2 had 30 (43 +/- 2 years old, ranging 17 to 65, 9 male and 21 female) with 2 single, 20 double, and 8 heart-lung transplantations. The recipient age was significantly (p = 0.004) higher in group 2, and group 2 had significantly older (35 +/- 3 vs 26 +/- 1, p = 0.002) and more female donors (73% vs 41%, p = 0.007) compared with group 1. The actuarial survival was significantly (p = 0.004) better in group 2 with 86% at 1 year, 75% at 5 years, and 66% at 10 years compared with group 1 with 58% at 1 year, 39% at 5 years, and 27% at 10 years. With our current pulmonary protection and immunosuppression, the long-term outcome of lung and heart-lung transplantation for idiopathic pulmonary arterial hypertension is excellent.

Advantages of peritoneal dialysis in comparison to hemodialysis, in cardiac allograft recipients with end stage renal disease

End stage renal disease is a serious complication in heart or heart-lung transplant recipients and is associated with high morbidity and mortality. The majority of these patients are currently treated with hemodialysis. Since there are no randomized control trials comparing hemodialysis to peritoneal dialysis in this patient population, the potential beneficial effects of peritoneal dialysis remain largely unknown. We compared the clinical outcome of such patients on peritoneal dialysis with another group on hemodialysis. Our results indicate that patients on peritoneal dialysis had fewer episodes of congestive heart failure, fluid overload and a lower overall hospitalization rate, despite having worse cardiac function than patients on hemodialysis.

Candida dubliniensisMeningitis as Delayed Sequela of TreatedC. dubliniensisFungemia

We present a case of Candida dubliniensis meningitis that developed 2 months after apparently successful treatment of an episode of C. dubliniensis candidemia in a heart-lung transplant recipient in Australia. This case highlights the importance of follow-up in patients with candidemia or disseminated infection, especially in immunosuppressed patients.

42: Lactobacillus acidophilus May Help To Decrease Recurrences and Ameliorate Severity of C. difficile-Associated Diarrhea in Lung Transplant Recipients

cially methicillin-resistant strains (MRSA) are common following lung transplantation. Vancomycin is commonly employed to treat these infections, but has several drawbacks including need for intravenous (IV) administration for systemic infection and the promotion of vancomycin-resistant enterococci. We reviewed our experience with linezolid for MRSA and the relative efficacy with vancomycin. Methods and Materials: We queried our transplant infectious disease database at our center, consisting of 2200 infection encounters in 370 lung and heart-lung transplant recipients (LTRs). We identified 93 episodes of staphylococcus aureus respiratory infection (70 were MRSA) by bronchoscopic culture using consensus definitions and evaluable data was available for 92 subjects; 34 were treated initially with oral linezolid and compared these to 58 similar cases treated with IV vancomycin. Effectiviness was judged by eradication of the organism on a follow-up bronchoscopic fluid culture. Results: Oral linezolid eradicated 50% (17 of 34) of all staphylococcal infections by time of subsequent bronchoscopy and vancomycin was similarly effective in 49% of the cases. Conclusions: LTRs who recieved oral linezolid had similar rates of eradication of staphylococcus on follow-up BAL compared to those who recieved IV vancomycin. Oral linezolid may represent an alternative choice for treatment of staphylococcus aureus respiratory infections in LTRs. Further study of relative cost of each therapy and tolerance are ongoing.

Quantification of Epstein-Barr Virus–DNA Load in Lung Transplant Recipients: A Comparison of Plasma versus Whole Blood

Monitoring of the Epstein-Barr virus-DNA load is frequently used to identify patients at risk for post-transplant lymphoproliferative disease (PTLD). Epstein-Barr virus DNA can be measured in the plasma and whole blood serum compartments. We compared levels of Epstein-Barr virus DNA in whole blood and plasma using a real-time TaqMan polymerase chain reaction assay in 100 consecutive paired whole blood and plasma samples from 25 lung and heart-lung transplant recipients with detectable whole blood Epstein-Barr virus-DNA load (>2,000 copies/ml). A correlation (r2) of 0.58 (p < 0.001) was observed between both measurements, whereas of the positive whole blood samples (>2,000 copies/ml), only 17 samples (18%) were also positive in plasma. These results indicate that by virtue of its sensitivity, whole blood rather than plasma may be the preferable specimen for the detection of Epstein-Barr virus DNA in lung transplant recipients.

Risk Factors for Chronic Renal Dysfunction in Lung Transplant Recipients

Several factors predispose to renal dysfunction (RD), a common complication of solid organ transplants. We evaluated the impact of clinical and laboratory parameters on the decline of renal function in lung and heart-lung transplant recipients. We enrolled 45 patients who survived more than 6 months after transplantation, had normal renal function and urinalysis before the surgery. The prognostic value of variables for the occurrence of RD was calculated by univariate analysis. Thirty patients developed RD, defined as doubling of serum creatinine or creatinine steadily >1.5 mg/dL after a median time of 12 months. Serum creatinine above 0.9 mg/dL during the month preceding lung transplant, systolic blood pressure above 130 mmHg, and pretransplant idiopathic pulmonary hypertension were significantly associated with the development of RD. Our findings indicate that increased systolic blood pressure, reduced glomerular filtration rate, and idiopathic pulmonary hypertension are risk factors for chronic RD in lung transplant recipients.

Screening for PTLD in lung and heart–lung transplant recipients by measuring EBV DNA load in bronchoalveolar lavage fluid using real time PCR

Pediatric L-HLTx recipients are at risk for developing PTLD with the lung being a primary site of disease. We hypothesized that BALF is a better sample than peripheral blood for measuring EBV DNA load in this high-risk population. Archived BALF specimens from pediatric L-HLTx recipients with and without PTLD were assayed for EBV DNA load using a quantitative real time TaqMan PCR assay. These values were compared with values determined in peripheral blood by a competitive PCR assay. Fifty-five BALF specimens from 16 L-HLTx patients were evaluated. Three patients with PTLD had mean BALF EBV DNA load values almost 50-fold higher than subjects without PTLD (4.6 x 10(5) copies/mL vs. 1.0 x 10(4) copies/mL). Patients who were EBV seronegative pretransplantation (i.e., high risk for PTLD) had elevated EBV DNA load values vs. patients who were EBV seropositive pretransplantation, regardless of the diagnosis of PTLD (mean values of 3.2 x 10(5) copies/mL vs. 1.1 x 10(4) copies/mL). Lastly, BALF analysis identified all subjects with PTLD, whereas peripheral blood analysis identified only one of these cases. Therefore, it can be concluded that monitoring EBV DNA load in BALF following L-HLTx facilitates detection of PTLD in high-risk patients and may be superior to peripheral blood assays.

Paradoxical worsening of tuberculosis in a heart–lung transplant recipient

We report on a heart-lung transplant recipient who presented with pulmonary tuberculosis (TB) 2.5 months after transplantation and then developed a paradoxical reaction after 4 months of adequate anti-TB treatment. She eventually recovered with anti-TB and high-dose steroid treatments. Using sequential bronchoalveolar lavages, we assessed the inflammatory response in the lung and investigated the alveolar immune response against a Mycobacterium tuberculosis antigen. The paradoxical reaction was characterized by a massive infiltration of the alveolar space by M. tuberculosis antigen-specific CD4(+) T cells and by the presence of a CD4(-)CD8(-) T lymphocyte subpopulation bearing phenotypic markers (CD16(+)/56(+)) classically associated with NK cells. This case report illustrates that even solid organ transplant recipients receiving intense triple-drug immune suppression may be able to develop a paradoxical reaction during TB treatment. Transplant physicians should be aware of this phenomenon in order to differentiate it from treatment failure.

Predictors of Chronic Kidney Disease in Long-Term Survivors of Lung and Heart-Lung Transplantation

Renal insufficiency is common after non-renal organ transplants. The predictors of long-term renal outcomes are not well established. A total of 219 lung and heart-lung transplant recipients surviving more than 6 months after transplantation were studied to determine predictors of time to doubling of serum creatinine and end-stage kidney disease (ESKD) with death as a competing risk. Median follow-up was 79 months (range 9-222 months). Baseline estimated glomerular filtration rate (GFR) was 96.3+/-34.5 mL/min/1.73 m2. One hundred twenty-two recipients (55%) doubled their serum creatinine, 16 (7.3%) progressed to ESKD and 143 (65%) died. The majority of recipients who survived >6 years had a GFR<60 mL/min at both 1 and 7 years. Most of the loss of renal function occurred in the first year post-transplant. Older age at transplant, lower GFR at 1 month and cyclosporine use in the first 6 months predicted shorter time to doubling of serum creatinine when death was handled as a competing risk. Based on this prevalence data and using GFR decay and death as study endpoints, we offer sample size estimates for a prospective, interventional trial that is aimed at slowing or preventing the progression of kidney disease.

Are Heart-Lung Transplant Recipients Protected From Developing Bronchiolitis Obliterans Syndrome?

Heart-lung transplant recipients, when compared with heart transplant recipients, are relatively spared from allograft coronary artery disease. This study was undertaken to investigate whether heart-lung transplant recipients are also spared from experiencing bronchiolitis obliterans syndrome (BOS) when compared with double-lung transplant recipients. In addition, the risk factors for developing BOS after lung transplantation were analyzed. Heart-lung and bilateral sequential double-lung transplant recipients were reviewed retrospectively from 1990 to 2000 using the Stanford Transplant Database. The heart-lung transplant group consisted of 77 heart-lung transplant recipients and the double-lung transplant group consisted of 51 double-lung transplant recipients. The rates of BOS, survival, acute rejection, and cytomegalovirus infection at 1, 3, and 5 years were measured. There were no significant differences in patient demographics between the two groups. Rates of survival and acute rejection were similar in the two transplant groups. The incidence of cytomegalovirus infection was significantly higher in heart-lung transplant recipients. Freedom from BOS was similar in the two transplant groups. Risk factors for the development of BOS in the heart-lung and double-lung transplant recipients included male donor, younger recipient age, a diagnosis other than cystic fibrosis, nonuse of cardiopulmonary bypass, and the use of OKT3 induction therapy. Heart-lung transplant recipients exhibit BOS at a rate similar to double-lung transplant recipients. The immunoprotective effect the lung allograft presumably provides the heart is not reciprocated by the heart in preventing the development of BOS.

Colon and Rectal Complications after Heart and Lung Transplantation

Gastrointestinal complications of solid organ transplantation have been well described, but little attention has been paid to colorectal disorders in particular. The purpose of this study was to identify the incidence and severity of colorectal complications among a large cohort of heart and lung transplant recipients. We reviewed the medical records of heart, lung, and heart-lung transplant recipients at a single institution between 1978 and 2004. Complications were identified based on need for consultation, endoscopy, or operation by a colorectal surgeon after transplantation. Of 1,012 patients who received transplantations (530 heart, 435 lung, 47 heart-lung), 56 patients (6%) required evaluation for 84 colorectal problems. Incidence of complications was 7% in lung transplant recipients, 6% in heart-lung transplant recipients, and 4% in heart transplant recipients. Forty-four events (52%) were considered major (diverticulitis, perforation, malignancy, and other) and 40 (48%) were minor (polyps, pseudo-obstruction treated medically or endoscopically, benign anorectal disease, and other). Twenty-three (27%) required colectomy and 9 (10%) necessitated anal operation. Thirty-six (43%) required less-invasive interventions (endoscopy, minor anorectal procedures, and other). Eighteen (21%) were treated with medical therapy alone. Six patients died from colorectal disease (7%). Colorectal complications are a considerable source of morbidity and mortality after heart and lung transplantation. These complications occur more frequently in patients who undergo lung and heart-lung transplantation as compared with heart transplantation alone.

Adherence to the Therapeutic Regimen in Heart, Lung, and Heart-Lung Transplant Recipients

Optimal outcome after heart, lung, and heart-lung transplantation can only be obtained if patients are supported in adhering to a lifelong therapeutic regimen. The transplant patient's therapeutic regimen consists of a lifelong medication regimen, including immunosuppressive drugs; monitoring for signs and symptoms related to complications; avoidance of risk factors for cardiovascular disease and cancer (ie, diet and exercise prescriptions, nonsmoking); avoidance of abuse/dependence of alcohol or illegal drugs, as well as attending regular clinical checkups. Nonadherence to all aspects of this regimen is substantial. Nonadherence has been related to negative clinical outcome in view of acute rejections, graft vasculopathy, higher costs, and mortality. This review focuses on the prevalence, correlates, and consequences of nonadherence to the therapeutic regimen in heart, lung, and heart-lung transplantation. The current state of the-art on adherence-enhancing interventions is reported. Priorities for future research are outlined.

Physical Functional Outcomes After Cardiothoracic Transplantation

The study of patient healthcare outcomes after cardiothoracic transplantation has increased substantially over the last 2 decades. Physical function after heart, lung, and heart-lung transplantation has been studied using both subjective and objective measures. The majority of reports in the literature on physical function after cardiothoracic transplantation are descriptive and observational. The purposes of the article are to review and critique the existing literature on cardiothoracic recipients' subjective and objective physical function, including respiratory function for heart-lung and lung transplant recipients. In addition, the literature on sexual function in cardiothoracic recipients is examined, the gaps in the literature are identified, and recommendations are given for future research.