Advances in immunosuppression after lung transplantation.

Immunosuppression in transplantation has experienced changes in recent years as a result of the introduction of new drugs that act upon the different pathways of the host immune response with the purpose of securing more individualized immune suppression, with fewer side effects. Although following in the steps of other solid organ transplant modalities, lung transplantation, because of its special characteristics, has not yielded similar middle- and long-term results. Improved understanding of the underlying rejection mechanisms, the pharmacodynamic control of drugs, new administration routes designed to reduce the side effects, and new drug substances or immune modulating processes will all contribute to improve the expectations associated to lung transplantation in the near future.

A multicenter study of valganciclovir prophylaxis up to day 120 in CMV-seropositive lung transplant recipients.

Seventy-six cytomegalovirus (CMV)-seropositive lung transplant recipients receiving valganciclovir (900 mg/day) for CMV prophylaxis were compared with a group of 87 patients receiving oral ganciclovir (3000 mg/day). Prophylaxis was administered to day 120 post-transplantation and follow-up was 1 year. In addition, a study was conducted on risk factors for CMV infection/disease. CMV disease incidence was 7.9% and 16.1% for valganciclovir and oral ganciclovir, respectively (p = 0.11). Patients receiving valganciclovir had fewer viral syndromes (2.6% vs. 11.5%, p < 0.05), a similar rate of tissue-invasive disease (5.2% vs. 4.6%, p = ns), longer time-to-onset of CMV infection/disease (197.5 vs. 155.2 days, p < 0.05), and a lower probability of infection/disease while on prophylaxis (1.3% vs. 12.6%, p < 0.01). Nonetheless, leukopenia incidence was higher with valganciclovir (15.8% vs. 2.3%, p < 0.01), as was the need for treatment withdrawal due to adverse effects (11.8% vs. 1.1%, p < 0.01). CMV infection was similar in both groups (32.9% vs. 34.5%). Induction therapy with basiliximab and glucocorticosteroid treatment were independent risk factors for developing CMV infection/disease. In conclusion, valganciclovir prophylaxis results in a low incidence of CMV disease in lung transplant recipients and appears more effective than oral ganciclovir. Despite the comparatively higher incidence of adverse events with valganciclovir, the drug can be considered safe for prophylaxis.

Development of neoplasms during lung transplantation follow-up.

OBJECTIVE: Lung transplant patient survival has significantly improved over the last 2 decades, which has resulted in an increased incidence of malignant disease. We undertook a descriptive, retrospective study of our series of transplant patients. PATIENTS AND METHODS: The study included 129 transplantations from 1999 to 2006. Ten patients (7.75%) developed 11 neoplastic processes during the follow-up period. RESULTS: In these 10 patients with neoformative processes (group 1), 40% were male and 60% female, compared with 62% male and 38% female in the neoplasia-free group (group 2). The overall mean age was 50.5 +/- 15.4 years in group 1 and 48 +/- 14 years in group 2. The neoplasias were: lymphomas (2) and tumors in the urinary tract (2), colon (2), kidney (1), skin (2), breast (1), and native lung (1). The median time from organ transplantation to diagnosis was 21 +/- 16 months. Of the 10 patients in group 1, 60% died, within a median of 9 months after diagnosis. Treatment consisted of surgery in 4 patients, chemotherapy in 5, and chemoradiotherapy in 1. The immunosuppression was changed after cancer diagnosis in 30% of the patients. CONCLUSIONS: Pharmacological immunomodulation caused a higher incidence of malignant disease, in addition to a worse prognosis for these diseases, which demonstrated the importance of adjusting the dose and searching for adequate therapeutic combinations.

Efficiency and safety of inhaled amphotericin B lipid complex (Abelcet) in the prophylaxis of invasive fungal infections following lung transplantation.

BACKGROUND: Invasive fungal infections (IFIs) in patients undergoing lung transplantation (LT) are associated with significant mortality. Previous studies have shown the efficacy of aerosolized amphotericin B deoxycholate and oral fluconazole for antifungal prophylaxis. Evolving data show a potential advantage of prophylaxis with lipid-based formulations of amphotericin B in the prevention of IFIs. We reviewed the incidence of IFIs among patients receiving aerosolized amphotericin B lipid complex (ABLC) in LT. METHODS: We undertook a retrospective review of the results of our antifungal protocol in a cohort of 60 LT patients. We analyzed the efficiency, safety, and tolerability of 50 mg of aerosolized ABLC administered postoperatively for IFI prophylaxis once every 2 days for 2 weeks and then once per week for at least 13 weeks. In addition, these transplanted patients received fluconazole (200 mg/d) during the first 21 days posttransplant. The prophylaxis-related efficiency and safety were quantified for IFIs and adverse events (AEs) for 6 months after study drug initiation. RESULTS: Prophylaxis was efficient in 59 (98.3%) patients. Only one patient developed a possible IFI, due to Aspergillus fumigatus. Four patients presented nausea and vomiting as an AE, although aerosolized amphotericin B was ongoing. CONCLUSIONS: Nebulized ABLC was effective, safe, and well tolerated for the prophylaxis of aspergillosis in lung transplant patients during the early posttransplant period.

Metachronous Pulmonary Neoplasms in Lung Transplantation-When They Arise in the Donor Lung: A Case Report.

Lung cancer (LC) is uncommon among lung transplant recipients, being most often described in the native lung of single-lung transplant recipients. Its appearance in the transplanted lung is a very uncommon phenomenon, in which donor and recipient factors appear to be involved. We present a case of 2 distinct metachronous lung neoplasms diagnosed in the transplanted lung of a non-smoker patient with progressive massive silicosis (PMS), who underwent left unipulmonary transplantation at 39 years. The donor was a smoker and thoracic computed tomography (CT) performed before the organ collection showed no abnormalities. Thirty months after transplantation, a new node with significant avidity in positron emission tomography (PET)-CT was diagnosed in the upper left lobe (ULL). The Thoracic Surgery team chose to proceed directly to surgery with atypical resection of the nodule. Anatomopathologic study revealed an epidermoid carcinoma (pT1aNx). Multidisciplinary group decided clinical surveillance; however, 2 years later, the appearance of 2 new nodules in the ULL (PET-CT positive) was observed. It was again decided to proceed to the surgery with a second atypical resection. The anatomopathologic study of one nodule revealed pulmonary adenocarcinoma (pT1aNx), and the other was compatible with epidermoid carcinoma (pT1aNx). One month later, the patient was hospitalized with a pulmonary abscess and posteriorly developed a probable acute allograft rejection, eventually dying at the age of 44, 51 months after transplantation. This case raises relevant questions regarding the donor selection criteria and the approach to LC diagnosed in the post-transplantation period.

Prevalence and management of gastrointestinal complications in lung transplant patients: MITOS study group.

INTRODUCTION: No studies have yet been performed to evaluate the prevalence of gastrointestinal (GI) complications in solid organ transplant recipients in Spain. MATERIALS AND METHODS: An observational, cross-sectional study to evaluate the prevalence and management of GI complications in transplanted patients was conducted via a written questionnaire given to doctors at their practice. RESULTS: A total of 58 lung transplant recipients were included. Their mean age was 52.6 +/- 10.8 years; 65% of the patients were men; and the mean time since the transplant was 2.1 +/- 2.3 years. GI complications were seen in 48.6% of the lung transplant patients. Regarding the management, the most frequently used measure was the prescription of gastric protectors (70.5%). In seven patients, the immunosuppressive treatment was also modified (reduced, discontinued temporarily, or discontinued permanently); however, the figure is so low that no conclusions can be drawn from this result. CONCLUSIONS: The prevalence of GI complications in lung transplant was over 50%, and these complications affected patients' daily activities in most cases. In lung transplant recipients, there was a higher prevalence of nausea and abdominal pain and a lower of diarrhea and dyspepsia than what was observed in other type of transplant recipients.

Conversion from cyclosporine to tacrolimus stabilizes the course of lung function in lung transplant recipients with bronchiolitis obliterans syndrome.

Bronchiolitis obliterans syndrome (BOS) continues to be the main factor limiting the long-term survival of lung transplant recipients. The objective of this study was to prospectively assess the impact of conversion from cyclosporine (CsA) to tacrolimus on lung function in patients who developed BOS while receiving CsA-based immunosuppressive therapy. A total of 79 patients with BOS were included in the study. Sixty percent of patients had stage II or III BOS according to the International Society for Heart and Lung Transplantation criteria. Mean time from transplantation was 30.4 +/- 21.9 months and all patients were on CsA therapy at enrollment in the study, with mean trough levels of 232.75 +/- 98.26 ng/mL. After conversion, tacrolimus trough levels were 11.0 +/- 3.6 ng/mL at 3 months and 9.0 +/- 3.4 ng/mL at 12 months. Sixteen deaths occurred during the first year postconversion, 56% of which were due to respiratory failure. Comparison of forced expiratory volume in 1 second (FEV(1)) preconversion versus postconversion showed a change in the slope of the FEV(1)-time curve. The slope of the preconversion curve was -0.44 versus a zero slope, whereas the slope of the postconversion curve was 0.005, with a statistically significant difference between both slopes. This change in slopes, which was also seen in FEV(1%), suggests that lung function loss closed after conversion from CsA to tacrolimus supporting this therapeutic strategy in lung transplant recipients with BOS treated with CsA.

Steroid withdrawal in lung transplant recipients.

OBJECTIVE: Many of the long-term complications in lung transplantations are secondary effects of immunosuppression. Corticosteroids are partially responsible for the development of osteoporosis, raised blood pressure, diabetes, muscular disorders, gastric ulcers, and other conditions. We analyzed the long-term result of steroid withdrawal in our lung transplant recipients. MATERIALS AND METHODS: When respiratory function stabilized, to avoid secondary effects, steroid treatment was withdrawn in 34 of the 375 lung transplant patients in our centers We evaluated the characteristics of the donors and recipients, their compatibility, the pre, and post-steroid withdrawal complications, and type of immunosuppressant. RESULTS: The mean age of patients was 42 +/- 7 years and of donors, 25 +/- 9 years. The primary diseases were: 15 emphysema, six pulmonary fibrosis, 10 cystic fibrosis, and three primary pulmonary hypertension. Twenty seven patients had double lung transplants and seven single lung. The mean steroid withdrawal period was 881 +/- 237 days posttransplantation. The most frequent treatment regimen at the time of steroid withdrawal was cyclosporine, azathioprine, and minimal steroid doses. Six recipients had to be restarted on steroids one patient who required a kidney transplant, three cases due to an infectious process with a differential diagnosis of rejection, and two cases due to loss of FEV1 (forced expiratory volume in 1 s), suggestive of chronic rejection. There was an improvement in blood pressure in five patients, in plasma cholesterol and triglyceride levels in eight patients, and insulin withdrawal in two diabetic patients. CONCLUSIONS: Steroid treatment may be suspended 2 to 3 years, posttransplant in selected lung transplant recipients. The usual patient profile shows few rejection episodes with cyclosporine and azathioprine immunosuppression. What is notable is the low mean age of donors. Close clinical monitoring and lung function testing are of major importance in the weeks following steroid withdrawal.

Comparative study of basiliximab treatment in lung transplantation.

OBJECTIVE: This study compared the incidence of acute or chronic rejection and adverse events in lung transplant patients receiving induction basiliximab versus controls not receiving treatment. MATERIALS AND METHODS: Basiliximab was administered to 15 patients with impaired renal function, advanced age, or high surgical risk, (group I). The mean age was 48.9 years; nine were double-lung and six single-lung grafts. They were compared to 13 lung transplants performed in 2001 (mean age 43.6 years, 11 double lung and two single lung [group II]). RESULTS: The incidence of acute rejection was 13.3% in group I versus 38.5% in group II (P = .19, OR 4.06), with chronic rejection in 20% and 38.5% of cases, respectively (P = .4, OR 2.5). No significant differences were observed in the incidence of infections or malignancies. Nor were there any direct adverse events due to the administration of the drug. The estimated 2-year survival was 80% for group I and 54% for group II (P = .14). CONCLUSIONS: Basiliximab has a trend to reduce the rate of acute and chronic rejection in lung transplant recipients, with no increased incidence of infections or malignancies. The 2-year survival for patients treated with basiliximab was better than the control group, despite including high risk transplant patients.

Basiliximab in lung transplantation: preliminary experience.

BACKGROUND: Basiliximab is a chimeric anti-interleukin-2 monoclonal antibody that has shown safety and efficacy in the prophylaxis of acute organ rejection in renal, liver, heart, and kidney-pancreas transplantation (Tx). The aim of this study was to present our initial experience with the use of Basiliximab in lung Tx. METHODS: Basiliximab (2 doses of 20 mg on day 0 and day 4) was administered to 16 patients treated with cyclosporine, azathioprine, and steroids between September 13, 2001 and August 26, 2003, including 12 men and 4 women patients with a mean age of 56.5 years (range, 19-69). The indication for use in transplantations were: reduced renal function (n = 14), post-Tx acute renal failure (n = 1) and steroid-resistant acute rejection (n = 1). Eight double-lung and eight single-lung Tx were performed for emphysema (n = 6), idiopathic pulmonary fibrosis (n = 7), silicosis (n = 2), and cystic fibrosis retransplantation (n = 1). RESULTS: The incidence of acute rejection was 16.6% (2 patients). Infections included cytomegalovirus (CMV) 33.3% (n = 4), bacterial 16.6% (n = 2), and fungal 8.3% (n = 1). Two patients died in the postoperative period and another at 3 months. There was no reaction to the medicine, and no malignancies or Bronchiolitis Obliterans Syndrome (BOS) during a follow-up period of more than 1 year in 10 patients. CONCLUSION: Basiliximab appeared to reduce the incidence of acute organ rejection and showed a good safety profile in terms of infections and adverse events.

Urgent lung transplantation in Spain.

BACKGROUND: Lung donors are scarce and lung transplantation resources are limited. Because urgent lung transplantation (ULT) is assumed to yield poor results, its use is controversial. We assessed the outcome of patients who received ULT seeking to determine effectiveness and risk factors. PATIENTS AND METHOD: We collected data from every ULT performed in Spain during 5 years (1998-2002). The survival of patients was studied using Kaplan-Meier, Cox regression, and chi-square statistical analyses. We compared outcomes and perioperative mortality (over 30 days) for ULT procedures, analyzing the influence of certain variables (age, type of transplant, diagnosis, indication, and time on waiting list). RESULTS: Among 109 patients proposed for the procedure, 73 ULT were performed during the period. The most frequent indications were pulmonary fibrosis (19 cases) and cystic fibrosis (19 cases), showing the worst and the better survival rates, respectively. The bad prognosis, determined mainly by per operative mortality rate (35.62%), was significantly affected by age (worse for patients older than 40 years) and type of LT (single worse than double; P < .05). A longer time waiting for ULT also showed a worse prognosis (P < .005). CONCLUSIONS: Long-term survival after ULT shows that the procedure is effective and efficient for a select group of patients, despite the high per operative risk. ULT should be reserved for younger patients. It also requires performance in a short period (just a few days), initially rejecting a single lung transplant, provided that the patient is adequately monitored.

Prevalence and Diagnosis of Chronic Kidney Disease in Maintenance Lung Transplant Patients: ICEBERG Study.

BACKGROUND: Chronic renal dysfunction (CRD) after lung transplantation (LT) is a common and noteworthy complication associated with increased morbidity and mortality rates. The study objectives were to determine the prevalence of CRD according to different diagnostic criteria and describe its therapeutic management. METHODS: This observational, multicenter, retrospective study included LT patients with ≥ 2 years of evolution. CRD was defined according to 2 different methods: (1) by the physician's subjective clinical criteria and (2) by analytical criteria (estimated glomerular filtration rate [eGFR] by Modification of Diet in Renal Disease of ≤ 59 mL/min). RESULTS: We included 113 patients; 65.5% were men and the mean age at transplant was 49.1 (12.6) years. At 6 months after transplant, approximately half of patients had CRD according to analytical criteria, and, at 2 years after transplantation, the prevalence rose to 80%. Although clinical prevalence and analytical prevalence were similar (68.8% and 78.6%), a weak concordance was observed (Kappa index: 0.6). Among patients who were not classified as having CRD according to clinical criteria, 40.0% (14/35) were diagnosed with CRD according to analytical criteria. None of the patients underwent renal biopsy, and 5.1% of patients required dialysis. In 77.0% of patients with clinical CRD diagnosis, the immunosuppressive regimen was modified: reduction of isolated calcineurin inhibitors (CNIs) (35.0%), CNIs decreased with mycophenolic acid change (23.3%), and CNIs lowering with mammalian target of rapamycin introduction (6.7%). In a multivariate logistic regression model, the independent factors associated with CRD were an older recipient age, low body mass index (BMI) at transplant, treatment with cyclosporine/azathioprine, and low eGFR at the first month after transplant. CONCLUSIONS: We found a high incidence of CRD at the first year after transplantation, which increased subsequently. Moreover, CRD was considerably underestimated by physicians' subjective clinical criteria. End points related to CRD development were older age, low BMI, azathioprine use, and low eGFR during the first month after transplant. The latter finding provides an opportunity to implement prevention strategies.

Postoperative surgical complications after lung transplantation.

This is a review article on the main postoperative complications after lung transplantation: airways complications, vascular complications, pleural complications, surgical wound complications, and abdominal complications. Incidence data, severity, and major management regimens are reported. Postoperative complications after lung transplantation result in a significantly increased morbidity and mortality, with early diagnosis and therapy being extremely important.

Antifungal prophylaxis during the early postoperative period of lung transplantation. Valencia Lung Transplant Group.

INTRODUCTION: Fungal infections occur frequently in lung transplant patients, with the highest risk being in the early postoperative period (the initial hospitalization after lung transplantation). Aspergillus is responsible for more than half of all fungal infections, and Aspergillus has even been considered a contraindication for lung transplantation because of its difficult therapy and frequently fatal outcome. The aim of this article is to evaluate the success of an antifungal prophylaxis protocol to prevent fungal infection in the immediate postoperative period in lung transplant recipients. MATERIAL AND METHODS: From March 1994 to March 1997, we performed 52 lung transplants in 31 men and 21 women who received antifungal prophylaxis with fluconazole, 400 mg/d, and aerosolized amphotericin B, 0.6 mg/kg/d, during the postoperative period. RESULTS: The mean (+/- SD) postoperative period duration was 49 +/- 27.5 days. No fungal infections were observed during this period, and all patients provided negative cultures. We also found no toxicity related to antifungal drugs. The dose of cyclosporine was easily adjusted in every recipient according to blood levels so that effective immunosuppression was not compromised. DISCUSSION: In our study, the removal of the lungs and antifungal prophylaxis with fluconazole and aerosolized amphotericin B prevented fungal infection in the postoperative period in all 52 lung transplant recipients.

Gastroplasty with partial or total plication for gastroesophageal reflux: manometric and pH-metric postoperative studies.

From January, 1975, to December, 1980, 83 patients with sliding hiatal hernia, gastroesophageal reflux, or both were treated using a modified Collis gastroplasty associated with either partial or total gastric application. When partial plication was used, the five-year clinical results were considered satisfactory in 27 out of 35 patients (77%). When total plication was used, the results were satisfactory in 41 out of 46 patients (89%) after follow-up ranging from 12 to 60 months (average, 36 months), but no symptoms of gastroesophageal reflux reappeared in any patient. In patients undergoing partial plication, the mean preoperative high-pressure zone of 11.20 +/- 8.19 mm Hg increased after operation to 17.31 +/- 10.50 mm Hg, but in the second postoperative studies the value decreased to 13.69 +/- 7.24 mm Hg. When 360 degrees plication was used, the preoperative value of the high-pressure zone--9.36 +/- 4.80 mm Hg--increased after operation to 17.70 +/- 7.53 mm Hg but did not decrease significantly in the second postoperative studies: 16.46 +/- 7.99 mm Hg. When partial plication was used, the positivity of the abdominal compression test was 9 and 28% in the early and late postoperative studies, respectively. Using total plication, the percentage of positivity in the early and late postoperative periods was 0 and 2%, respectively. Concerning the acid reflux test, when partial plication was used, the test was positive in 3 out of 27 patients (11%) in the early postoperative studies and in 7 out of 30 (23%) one year later. For the total plication procedure, the percentage of positive tests was null in the first control and 3% in the second postoperative studies.

Bronchial fistula to the mediastinum in a heart-lung transplant patient.

We present a case of heart-lung transplantation complicated by bronchial perforation as the cause or consequence of prolonged lung infection. Periodic bronchoscopic and radiological follow-up showed resolution of the condition following adequate antibiotic and physiotherapeutic treatment.

Successful revascularization of large isolated tracheal segments.

The omentum has been shown to be of use in clinical and experimental revascularization of tracheobronchial anastomoses. We have evaluated the possibility of revascularizing large and completely isolated tracheal segments while preserving the main tracheal characteristics. Ten experiments were performed in dogs, introducing 10-14 cartilage ring tracheal segments enveloped in omentum into the abdomen. Revascularization resulted in all cases with preservation of tracheal consistency. In only two cases were small mucosal necrotic zones observed. The experimental model thus appears to be of use in the revascularization of large tracheal segments, with excellent preservation of both cartilage and mucosa.

Management of non-tumoral tracheal stenosis in 112 patients.

From January 1973 to August 1989, 112 patients with non-tumoral tracheal strictures were treated in our unit. In 102 patients, the stenosis followed respiratory support. Eighty-one patients were treated surgically; the rest required only endoscopic therapy. In 28 patients, surgical treatment followed failure of endoscopic management. Of the patients submitted to surgery an isolated tracheal stenosis was present in 54 cases while a laryngotracheal stricture was the lesion in the other 27. Tracheal resection and end-to-end anastomosis was performed in the former group. Rethi, Pearson and Couraud procedures, respectively, were carried out in the latter. We emphasize the difference in the results achieved in the first 5 years and those obtained in the last 10 years. In the former period, 7 reoperations were needed. On the other hand, although the overall mortality of both series was 9%, it decreased to 2% during the last 10 years. Excellent or good ultimate results were achieved in 92% of survivors. Finally, we stress the differences in the proportion of reinterventions and definitive failures in the surgical treatment of isolated tracheal stenosis compared to laryngotracheal strictures.

Blunt chest injuries in 1696 patients.

We review 1696 patients with blunt chest trauma. Road traffic accidents were the main cause of injury followed by domestic falls and labour accidents. Outdoor falls and sport accidents accounted for a small number of injuries. For clinical evaluation, Stoddart's score was used. The injuries were considered as minor in 710 patients, intermediate in 740 and severe in 246. Global in-hospital mortality was low (5%) but increased to 37% when only patients with multiple severe injuries were considered. Thoracic wall fractures were present in 1419 patients. Flail chest was diagnosed in 140 patients and pulmonary contusion in 275. Diaphragmatic rupture was present in 40 patients and tracheobronchial injury in 6. Cardiovascular injuries occurred in 55 patients. Associated extrathoracic injuries were seen in 611 patients: 923 patients were clinically observed and/or medically treated. An intercostal tube was inserted in 638 patients. Thoracotomy was undertaken in 105 patients. Surgical fixation for flail chest was carried out in 29 patients. The results were generally good: 9 patients did not need any mechanical ventilation and 11 were ventilated for a short period. No deaths were due to the surgical procedure. The authors maintain that a selective attitude restricting, but not ignoring, surgical stabilization is the best policy.

Tuberous sclerosis and pregnancy; report of a case with renal and pulmonary involvement.

Tuberous sclerosis is a very infrequent hereditary disease, usually defined by the triad of epilepsy, mental retardation and adenoma sebaceum, although alterations in other organs can exist. Tuberous sclerosis in its association with pregnancy has seldom been described in the literature. One such case is reported here; that of a 24-yr-old woman whose pulmonary involvement constitutes its differentiating characteristic. We make special mention of the improvement of the respiratory function, without any modification of the renal function, in contrast with other previously published cases. She gave birth spontaneously by vaginal via. Finally, we underline the importance of prenatal diagnosis and genetic advice for these patients.