Paula Moreno

Incidence, management and clinical outcomes of patients with airway complications following lung transplantation

OBJECTIVE Airway complications (AC) remain a significant contributing factor of morbidity after lung transplantation (LT). The aim of this study was to identify risk factors for AC, and to review the outcomes after endoscopic and surgical treatment. METHODS From 1993 to 2006, 255 patients underwent LT. Seven retransplants and 34 patients not surviving beyond 7 days were excluded. The remaining patients were: 124 double LT (DLT), 85 single LT (SLT), 3 lobar LT and 2 liver-DLT, comprising 343 bronchial anastomoses at risk. Donor lungs were flushed with either modified Eurocollins or Perfadex. Bronchial anastomoses were telescoped when needed. Donor and recipient variables were recorded and analyzed by univariate and multivariate tests to identify risk factors for AC, and to assess differences between both complicated and non-complicated groups. RESULTS Among 343 bronchial anastomoses, 31 presented AC (9%) in 27 patients (12.6%): 22 stenoses, 5 dehiscences, and 4 malacias, at 2.6+/-1.7 months post-transplant. Indications were 7 emphysema, 3 Alpha-1-antitrypsin deficiency, 12 cystic fibrosis (p=0.007), 4 pulmonary fibrosis, and 1 bronchiectasis. AC were observed in 4 SLT and 23 DLT (p=0.005). Incidence of AC did not differ between telescoped and non-telescoped anastomoses. By univariate analysis, AC were more frequent in grafts preserved with modified Eurocollins (p=0.033), CMV infection/disease (p=0.027) and airway colonizations post-transplant (p=0.021). Other donor and recipient variables did not differ between groups. By multivariate analysis, intubation longer than 72 h, DLT, and airway colonizations post-transplant remained independently associated with AC. Survival did not differ between groups. Most patients were successfully treated with endoscopic procedures; three required reoperation (lobectomy, pneumonectomy, retransplantation). AC related mortality was 1%. CONCLUSIONS The incidence of AC after LT is 12.6% with a related mortality of 1%, irrespective of the technique of bronchial anastomosis performed. DLT, airway colonizations, and prolonged intubation post-transplant are associated with AC. Either endoscopic procedures or surgical therapy resolve these complications in most cases.

Results of Lung Transplantation in Idiopathic Pulmonary Fibrosis Patients

Lung transplantation (OLT) remains the only available therapy for patients with end-stage idiopathic pulmonary fibrosis (IPF). The objective of this study was to review our experience of OLT for end-stage IPF (IPFLT) patients, seeking to identify variables associated with survival for comparison with outcomes of other indications for LT (OILT). From October 1993 to December 2009, we performed 310 consecutive OLT in 301 patients for treatment of various end-stage pulmonary conditions. The indications for OLT were: IPF (n=89, 30.5%) chronic obstructive pulmonary disease (n=82), cystic fibrosis (n=80), bronchiectasis (n=12), alfa-1-antitrypsin deficit (n=6), primary pulmonary hypertension (n=4), bronchiolitis obliterans (n=4), other conditions (n=15). We observed significant differences in the actuarial survival between the IPFLT and the OILT groups particularly at the expense of worse perioperative 30-day and early 1-year mortality in the IPFLT group. Upon univariate and multivariate analyses, the need for cardiopulmonary bypass, previous recipient ventilator dependence, and donor age>50 years were all associated with poorer survival rates among IPF patients. In our experience, survival did not differ between patients who underwent a single versus a bilateral sequential lung transplant (BSLT); however, BSLT cases were associated with short-term damage but long-term survival. The functional results in the IPFLT group were excellent. We observed significant improvements in the values of arterial oxygen pressure (PaO2), arterial carbon dioxide pressure (PaCO2), forced vital capacity (FVC%) and forced expiratory volume in 1 second (FEV1%) at 6, 12, and 36 months compared to their pretransplant baseline results.

Extended recipients but not extended donors are associated with poor outcomes following lung transplantation

OBJECTIVES Extended donors (EDs) are safely used to increase the donor pool in lung transplantation (LT), but their influence in critically ill patients (extended recipients [ERs]) remains controversial. We compared LT outcomes matching optimal donors (ODs) or EDs with optimal recipients (ORs) or ERs. METHODS Three hundred and sixty-five LTs were reviewed. ED criteria: age >55, PaO2/FiO2 < 350 mmHg, pulmonary infiltrates/purulent secretions and ischaemic times >6 h (single LT [SLT]) and >9 h (double LT [DLT]). ER criteria: pulmonary fibrosis or pulmonary hypertension, pretransplant intubation, age >60 years and bypass >2 h. Four groups were created: Group 1 (OD/OR), Group 2 (OD/ER), Group 3 (ED/OR) and Group 4 (ED/ER). Thirty-day mortality, primary graft dysfunction (PGD), onset of bronchiolitis obliterans syndrome (BOS), long-term survival and other transplant outcomes were compared between OD and ED, OR and ER and among the four groups of study. RESULTS There were 151 SLTs and 214 DLTs. Donors: OD (n = 229) vs ED (n = 136); PGD 8 vs 10% (P = 0.43); 30-day mortality 19 vs 20% (P = 0.53) and survival (1, 5, 10 and 15 years) 67, 47, 34, 26 vs 69, 53, 46 and 29% (P = 0.33). Recipients: OR (n = 182) vs ER (n = 183); PGD 7 vs 10% (P = 0.10); 30-day mortality 15 vs 23% (P = 0.04) and survival (1, 5, 10 and 15 years): 73, 57, 46, 30 vs 61, 42, 29 and 23% (P = 0.002). Four donor/recipient (D/R) groups: Group 1 (n = 122), Group 2 (n = 106), Group 3 (n = 61), Group 4 (n = 76); PGD 10, 6, 3 and 16% (P = 0.05); 30-day mortality 13, 26, 19 and 20%, respectively (P = 0.13); survival (1, 5, 10 and 15 years) 74, 55, 44 and 35% (Group 1), 55, 39, 22 and 16% (Group 2), 70, 59, 48 and 26% (Group 3) and 68, 47, 37 and 22% (Group 4) (P = 0.004). No differences in the onset of BOS were observed among the four study groups. CONCLUSIONS LT in critically ill recipients is associated with poor early and long-term outcomes, irrespective of the quality of the donor and length of ischaemic times.

Influence of donor–recipient gender mismatch on graft function and survival following lung transplantation

OBJECTIVES In current practice, donors and recipients are not matched for gender in lung transplantation. However, some data have suggested a possible effect of gender combinations on lung transplant outcomes. We examined whether donor-recipient (D/R) gender mismatch is related to adverse outcomes after lung transplantation in terms of early and long-term graft function and survival. METHODS We reviewed 256 donors and lung transplant recipients over a 14-year period. Patients were distributed into four groups: Group A (D/R: female/female), Group B (D/R: male/male), Group C (D/R: female/male), Group D (D/R: male/female). Donor and recipient variables were compared among groups, including early graft function, 30-day mortality, freedom from bronchiolitis obliterans syndrome (BOS), and long-term survival. RESULTS Group A: 57 (22%), Group B: 99 (39%), Group C: 62 (24%), Group D: 38 (15%) transplants (P = 0.001). Donor age was 29 ± 14, 27 ± 12, 33 ± 13 and 23 ± 12 years for Groups A, B, C and D, respectively (P = 0.004). Recipient age was 31 ± 15, 44 ± 17, 42 ± 16 and 30 ± 16 years for Groups A, B, C and D, respectively (P = 0.000). PaO2/FiO2 (mmHg) 24 h post-transplant was: Group A: 276 ± 144, Group B: 297 ± 131, Group C: 344 ± 133 and Group D: 238 ± 138 (P = 0.015). Primary graft dysfunction developed in 23, 14, 17 and 21% of recipients from Groups A, B, C and D, respectively (P = 0.45). Operative mortality was 4.4, 6.5, 5.2 and 2%, for recipients from Groups A, B, C and D, respectively (P = 0.66). Freedom from BOS was 73, 59 and 36% for gender-matched transplants vs 76, 67 and 40% for gender-mismatched transplants at 3, 5 and 10 years, respectively (P = 0.618), without differences among groups. A non-significant survival benefit was observed for female recipients, irrespective of the donor gender. CONCLUSIONS Donor-recipient gender mismatch does not have a negative impact on early graft function and mortality following lung transplantation. There is a trend towards a survival benefit for female recipients, irrespective of the donor gender.

Lung transplantation for cystic fibrosis: differential characteristics and outcomes between children and adults

OBJECTIVES The survival benefit of lung transplantation (LTx) for cystic fibrosis (CF) patients is well demonstrated. We aim to compare children and adult CF recipients to assess whether there are differences in survival and clinical outcomes, and to identify risk factors for mortality. METHODS A retrospective analysis of 442 consecutive LTx performed at our institution in a 20-year period was conducted. CF patients were distributed into two groups: children (age <18 years) and adults (age ≥18 years). Donor and recipient general demographic data, perioperative and postoperative factors including 30-day mortality, survival, primary graft dysfunction (PGD), complications, acute rejection (AR) and chronic lung allograft dysfunction (CLAD) were analysed and compared between groups. Univariable, Kaplan-Meier and Cox regression analyses were performed. RESULTS The study group included 120 consecutive CF patients: 50 children (13 ± 3 years) and 70 adults (25 ± 6 years) undergoing 111 bilateral, 4 lobar, 4 combined and 1 unilateral LTx. Comparative analysis (children versus adults): survival (overall; 5, 10 and 15 years) 57, 45, 35% vs 67, 55, 43% (P = 0.32); survival (1-year survivors; 5, 10 and 15 years): 75, 64, 46% vs 90, 75, 59% (P = 0.09); 30-day mortality: 14 vs 16% (P = 0.27); urgent LTx: 32 vs 17% (P = 0.04); use of cardiopulmonary bypass (CPB): 56 vs 28% (P = 0.002); intensive care unit stay: 20 ± 19 vs 10 ± 9 days (P = 0.006); AR episodes (n): 1.4 ± 0.7 vs 1.2 ± 0.8 (P = 0.004). Incidence of PGD and freedom from CLAD did not differ between groups. Predictors of mortality were: use of CPB (HR 3.12; 95% CI 1.33-7.35; P < 0.01), post-transplant diabetes mellitus (HR 2.49; 95% CI 1.13-5.43; P = 0.02) and pneumonia episodes within the first month post-transplant (HR 2.82; 95% CI 1.27-6.29; P = 0.01). CONCLUSION Paediatric CF patients usually present with poorer pre-transplant status, require CPB more frequently and have a higher incidence of post-LTx diabetes and infections. This might explain the trend towards a better long-term survival observed in adult CF patients.

Assessment of lungs for transplantation: a stepwise analysis of 476 donors.

OBJECTIVE This study aims to assess the suitability rates and the causes of lung-donor refusal, to determine which factors could be improved to expand the donor pool available for transplantation (LTx). METHODS Lung donors offered to our Lung Transplantation Unit from October 1993 to December 2007 were reviewed to assess the causes of unsuitability. The donor-lung evaluation was divided into three stages: stage 1 (PaO(2)/FiO(2) ratio, chest X-ray, bronchoscopic findings), stage 2 (donor-lung inspection and palpation) and stage 3 (assessment of grafts after harvesting). Variables from donors and recipients were analysed and compared between 1993-2001 (group A) and 2002-2007 (group B). An additional subgroup of extended donors was analysed to assess the recipient outcomes. RESULTS A total of 476 lung donors were assessed (278 men and 198 women; mean age 29+/-13 years). Causes of death were trauma in 255, intracranial bleeding in 202 and others in 19. As many as 273 donors were suitable for LTx (57%; 162 double LTx and 111 single LTx). Acceptability rates were 68%, 58% and 57% at stages 1, 2 and 3, respectively, and were significantly higher in group B than in group A (overall: 64% vs 54%; stage 2: 91% vs 79%), with no changes in stages 1 and 3. Abnormal bronchoscopy precluded LTx in 79 cases (16%). Group B donors were older (p=0.000), ventilated longer (p=0.07) and with shorter ischaemic times (p=0.000) than group A. In the recipients, primary graft dysfunction (PGD) (17% vs 15%) and 30-day mortality (11% vs 6%) did not differ between both the groups. No differences were observed between extended and ideal donors in terms of recipient 30-day mortality (extended 6% vs ideal 9%; p=0.315) and development of PGD (extended 21% vs ideal 15%; p=0.342). CONCLUSIONS Despite the high rate of organ donation in Spain, the acceptability rate remains low (57%), mainly due to failure to meet the criteria for acceptance at the early stages of donor-lung assessment. Improvements in multi-organ donor care must be made to expand the lung-donor pool. The use of extended donors does not seem to have a negative impact on recipient outcomes.

Results of Lung Transplantation in Patients With Cystic Fibrosis

Lung transplantation (LT) is the only available option for patients with cystic fibrosis (CF) with end-stage lung disease. We reviewed our experience with LT in patients with end-stage CF (CFLT) to identify variables associated with survival and to compare the results with other indications for LT (OILT). Between October 1993 and October 2007, we performed 259 consecutive LTs in 250 patients for treatment of various end-stage pulmonary conditions. The indications for LT were CF in 78 patients idiopathic pulmonary fibrosis in 76, COPD in 64, bronchiectasis in 11, alfa-1-antitrypsin deficit in 5, primary pulmonary hypertension in 4, bronchiolitis obliterans syndrome in 4, and other indications in 11. Our study group comprised 78 patients with CF (30.11%) (CFLT). We observed significant differences in the actuarial survival between the CFLT and OILT groups. Perioperative mortality and the incidence of bronchiolitis obliterans syndrome were comparable in both groups. We found that in patients with CF, LT performed under urgency code (mechanical ventilation) showed no significant difference from LT performed electively insofar as long-term survival, early death, or perioperative death. The functional results in the CFLT group were excellent. We observed significant improvement in PaO(2), PaCO(2), forced vital capacity, and forced expiratory volume in the first second of expiration at 6, 12, and 36 months compared with the pretransplantation baseline values.

Lung Cancer in Patients With Lung Transplants

OBJECTIVE The aim of our study was to describe the incidence of lung cancer in patients after lung transplantation (LT). MATERIALS AND METHODS We performed an observational, retrospective, descriptive study based on data from 340 patients undergoing lung transplantation between October 1993 and December 2010. We collected data about the donors, recipients, intra- and postoperative periods, and survivals. RESULTS We identified 9 (2.6%) patients who developed lung cancer after LT. Their average age was 56 ± 9.3 years (range, 18-63). All cases were men with 8/9 (88.8%) having received a single lung transplant. All cancers developed in the native lung. The indications for transplantation were: emphysema type chronic obstructive pulmonary disease (COPD; n = 5), idiopathic pulmonary fibrosis (n = 3), or cystic fibrosis (n = 1); 77% of them were former smokers. All of the COPD patient were affected. The interval from transplantation to diagnosis was 53.3 ± 12 months (range 24-86). Survival after cancer diagnosis was 49.3 ± 6.3 (range = 0-180) months. CONCLUSIONS LT was associated with a relatively high incidence of lung cancer, particularly in the native lung. In our series, lung cancer was related more to patients with emphysema-type COPD and a history of smoking. We believe that these patients should be closely followed to establish the diagnosis and apply early treatment.

Urgency-Code Lung Transplantation for Cystic Fibrosis: Experience and Results

Lung transplantation (LT) under urgency-code mechanical ventilation (UCMV) has been identified in the International Society for Heart and Lung Transplantation (ISHLT) Registry as a negative prognostic factor increasing the likelihood of mortality. The objective of this study was to review our experience of UCLT for with cystic fibrosis (CF) patients compared with elective LT (ELT). From October 1993 to October 2007, we performed 259 consecutive LTs in 250 patients, of whom 78 (31.20%) had CF. Our study group comprised CF patients who received UCLT (n = 23). The type of LT in the UCLT group was as follows: bipulmonary (18), left unipulmonary (2), and bilobar transplantation from cadavers (3). The UCLT group more often required cardiopulmonary bypass (CB) (P = .025), pulmonary tailoring (P = .030), and longer periods of pulmonary ischemia (P = .066) than the ELT group. We noticed a greater number of cases of pneumonia during the first postoperative month in the UCLT group. However, incidence of surgical complications, early and perioperative mortality, and episodes of acute and chronic rejection (bronchiolitis obliterans syndrome) did not differ between the groups. Survival rates at 1, 3, 5, and 10 years were 73.66%, 63.74%, 42.49%, and 42.49%, respectively, in the UCLT group (mean, 1927 [SE = 366] days) and 75.95%, 71.32%, 63.37%, and 63.37% in the ELT group (mean, 2946 [SE = 281] days; P = .3417). In our experience, UCLT in patients with CF is fully justified. Careful selection of such cases permits acceptable long-term survival rates to be achieved with no increase in early or perioperative mortality.

The Expression of the Ubiquitin Ligase SIAH2 (Seven In Absentia Homolog 2) Is Increased in Human Lung Cancer

Objectives Lung cancer is the leading cause of cancer-related deaths worldwide. Overall 5-year survival has shown little improvement over the last decades. Seven in absentia homolog (SIAH) proteins are E3 ubiquitin ligases that mediate proteasomal protein degradation by poly-ubiquitination. Even though SIAH proteins play a key role in several biological processes, their role in human cancer remains controversial. The aim of the study was to document SIAH2 expression pattern at different levels (mRNA, protein level and immunohistochemistry) in human non-small cell lung cancer (NSCLC) samples compared to surrounding healthy tissue from the same patient, and to analyse the association with clinicopathological features. Materials and Methods One hundred and fifty-two samples from a patient cohort treated surgically for primary lung cancer were obtained for the study. Genic and protein expression levels of SIAH2 were analysed and compared with clinic-pathologic variables. Results The present study is the first to analyze the SIAH2 expression pattern at different levels (RNA, protein expression and immunohistochemistry) in non-small cell lung cancer (NSCLC). We found that SIAH2 protein expression is significantly enhanced in human lung adenocarcinoma (ADC) and squamous cell lung cancer (SCC). Paradoxically, non-significant changes at RNA level were found, suggesting a post-traductional regulatory mechanism. More importantly, an increased correlation between SIAH2 expression and tumor grade was detected, suggesting that this protein could be used as a prognostic biomarker to predict lung cancer progression. Likewise, SIAH2 protein expression showed a strong positive correlation with fluorodeoxyglucose (2-deoxy-2(18F)fluoro-D-glucose) uptake in primary NSCLC, which may assist clinicians in stratifying patients at increased overall risk of poor survival. Additionally, we described an inverse correlation between the expression of SIAH2 and the levels of one of its substrates, the serine/threonine kinase DYRK2. Conclusions Our results provide insight into the potential use of SIAH2 as a novel target for lung cancer treatment.