Secondary pulmonary arterial hypertension: to treat or not to treat?

PURPOSE OF REVIEW: The purpose of this review is to review recent literature related to mechanisms and treatment options for 'secondary' (i.e., WHO Groups 3 and 5) pulmonary arterial hypertension (PAH). RECENT FINDINGS: Published randomized controlled trials, in general, do not support the use of approved therapies for 'primary' (i.e., WHO Group 1) PAH patients in patients with Group 3 PAH because of the small numbers of patients and inconsistent benefit. Therefore, we currently recommend against the use of these medications for Group 3 PAH. Similarly, there is limited evidence supporting the use of Group 1 PAH medications in Group 5 patients. In most patients with Group 5 PAH, treatment should be directed to the underlying disease. SUMMARY: The utility of PAH-specific therapy in WHO Group 3 PAH is unclear because of the small numbers of patients evaluated and inconsistent beneficial effects observed. There is limited evidence supporting the use of PAH medications in Group 5 patients, and they may be harmful in some cases.

Gender differences in long-term survival post-transplant: A single-institution analysis in the lung allocation score era.

The purpose of this study was to clarify the significance of recipient gender status on lung transplant outcomes in a large single-institution experience spanning three decades, we analyzed data from all lung transplants performed in our institution since 1986. Kaplan-Meier curves and Cox proportional hazard models were used to evaluate the effect of recipient characteristics on survival and BOS score ≥1-free survival. Logistic regression analysis was used to explore the association of gender with short-term graft function. About 876 lung transplants were performed between 1986 and 2016. Kaplan-Meier survival estimates at 5 years post-transplant for females vs males in the LAS era were 71% vs 58%. In the LAS era, females showed greater unadjusted BOS≥1-free survival than males (35% vs 25%, P=.02) over 5 years. Female gender was the only factor in the LAS era significantly associated with improved adjusted 5-year survival [HR 0.56 (95% CI 0.33, 0.95) P=.03]. Conversely, in the pre-LAS era female gender was not associated with improved survival. Female recipients showed significantly improved survival over 5 years compared to males in the LAS era. A prospective analysis of biologic and immunologic differences is warranted.

Lung transplantation for pulmonary sarcoidosis. Twenty-five years of experience in the USA.

OBJECTIVE: Lung transplantation is the ultimate treatment for end-stage pulmonary sarcoidosis. Post-transplant survival outcomes remain unclear. METHODS: Survival models were used to assess survival and graft outcomes in patients with sarcoid among 20,896 lung transplants performed in the USA. RESULTS: 695 lung recipients were transplanted for pulmonary sarcoidosis. Sarcoid lung recipients had similar median survival rate (69.7 months (IQR 60.2-79.3)) compared with the non-sarcoid lung recipients (63.1 months (IQR 61.4-64.8), p=0.88). In multivariate Cox regression, sarcoidosis was not independently associated with worse mortality (HR 0.96 (95% CI 0.85 to 1.08), p=0.51). Among the sarcoid lung recipients, double lung transplantation (HR 0.76 (0.58 to 0.99), p=0.04) and lung allocation score era (HR 0.74 (0.56 to 0.97), p=0.03) were associated with improved survival. CONCLUSIONS: Recipients of lung transplants for pulmonary sarcoidosis had similar outcomes compared with non-sarcoid lung recipients.

Calcineurin inhibitors and Clostridium difficile infection in adult lung transplant recipients: the effect of cyclosporine versus tacrolimus.

BACKGROUND: Tacrolimus (FK506) has a superior immunosuppressive effect compared with cyclosporine (CSA) without a significant increase in generalized infectious complications. Differences in specific infections such as Clostridium difficile (CDI) have not been reported. We investigated the relationship between calcineurin inhibitors and CDI, hypothesizing that choice of calcineurin inhibitor (CSA or FK506) after lung transplantation would have no effect on the incidence of CDI. METHODS: We performed a retrospective chart review of lung transplant recipients between June 1, 2000, and December 31, 2005, at a single institution. Positive CDI assays through December 11, 2011, were also recorded. We used Student's t- and chi-squared tests (α = 0.05) to compare CSA and FK506 groups. We calculated adjusted hazard ratios for CDI using Cox proportional hazard models. RESULTS: We identified 217 lung transplant recipients: 106 patients in the CSA group and 111 patients in the FK506 group. A total of 31 patients (27.9%) in the FK506 group developed CDI postoperatively compared with 20 patients (18.9%) in the CSA group (P = 0.16). The adjusted hazard ratio for CDI in the FK506 group was not significantly higher (1.53; 95% confidence interval, 0.78-2.98). There was no significant difference in the intensive care unit or total length of stay, in-hospital incidence rate, time to first CDI episode, or recurrence rate between groups. CONCLUSIONS: The CDI rates were not significantly higher in the FK506 group than the CSA group in our study. These data are consistent with previous studies on FK506 that show no increase in infectious complications over CSA, and demonstrate its continued safety in lung transplantation.

The rise of Clostridium difficile infection in lung transplant recipients in the modern era.

PURPOSE: Clostridium difficile infection (CDI) rates have been rising in recent years. We aimed to characterize CDI in lung transplant recipients in the modern era and hypothesized that CDI would increase the mortality risk. METHODS: We performed a retrospective chart review of patients undergoing transplantation at our center from 1/2006 to 7/2011. Attributes of CDI+ and CDI- groups were compared using Student's t- and chi-square tests (α = 0.05). Multivariate Cox proportional hazard models were used to control for confounding factors. RESULTS: Overall CDI incidence was 22.5%. Seven of 151 patients (4.6%) developed CDI during the initial hospitalization after transplantation (mean time 10.6 ± 6 d) while 27 patients (19.7%) developed CDI after discharge (mean time 467 ± 471 d). Incidence rate was 224.6 cases/100 000 patient-days compared to 110 cases/100 000 patient-days (rate for entire hospital). CDI was not predictive of mortality (HR 2.06, 95% CI 0.94-4.52). CONCLUSION: CDI rates in lung transplant recipients are high in the modern era. No risk factors for CDI were identified. Although not statistically significant, CDI+ patients had a higher risk of death. The economic burden of CDI and trend toward worse outcomes for CDI patients have important implications for post-operative surveillance of CDI-related complications and need for CDI prophylaxis.

Automatic event detection in lung transplant recipients based on home monitoring of spirometry and symptoms.

OBJECTIVE: The goal of this study was to develop, implement, and test an automated decision system to provide early detection of clinically important bronchopulmonary events in a population of lung transplant recipients following a home monitoring protocol. SUBJECTS AND METHODS: Spirometry and other clinical data were collected daily at home by lung transplant recipients and transmitted weekly to the study data center. Decision rules were developed using wavelet analysis of declines in spirometry and increases in respiratory symptoms from a learning set of patient home data and validated with an independent patient set. RESULTS: Using forced expiratory volume in 1 s or symptoms, the detection captured the majority of events (sensitivity, 80-90%) at an acceptable level of false alarms. On average, detections occurred 6.6-10.8 days earlier than the known event records. CONCLUSIONS: This approach is useful for early discovery of pulmonary events and has the potential to decrease the time required for humans to review large amount of home monitoring data to discover relatively infrequent but clinically important events.

Lung transplantation after hematopoietic stem cell transplantation.

INTRODUCTION: Pulmonary insufficiency following bone marrow transplant (BMT) is common and has significant associated mortality. Lung transplantation (LTX) is the only viable treatment for patients with end-stage pulmonary disease, but LTX after BMT is an uncommon event given the medical candidacy of the potential recipients. We sought to evaluate the short- and long-term outcomes of LTX in BMT recipients. METHODS: We performed a retrospective evaluation of our institution's longitudinal LTX and BMT databases. Demographic and outcomes variables were collected. RESULTS: We identified 639 LTX from January 1, 1988, through December 31, 2009, and 5525 BMT from program inception, March 21, 1974, through December 31, 2009. From the cross-referenced cohort, we identified four patients who had BMT followed by LTX. Our series was composed of two men and two women, with a mean age of 32.3 yr (range, 20-59 yr). Single LTX were performed in two recipients (50%). All patients had significant and expected morbidities related to their transplant immunosuppression. Three patients (75%) required cardiopulmonary bypass at the time of LTX. The two recipients who underwent bilateral LTX required open chest management and subsequent tracheostomy. All patients are still alive at follow-up (range, 19-119 months, median 39.5). CONCLUSION: Our study demonstrates that LTX in the setting of BMT is a high-risk operation with the potential for a tumultuous perioperative course. Despite this, good outcomes and survival are obtainable in carefully selected patients. Selection factors include clinically stable patients without active sepsis and preoperative optimization of nutrition in anticipation of a prolonged recovery. An experienced multidisciplinary team approach and a protocol-driven management plan are paramount for successful outcomes in this challenging population.

A randomized, placebo-controlled trial of aprotinin to reduce primary graft dysfunction following lung transplantation.

PURPOSE: Severe primary graft dysfunction (PGD) is the major early problem following lung transplantation. Aprotinin, a serine protease inhibitor, has many anti-inflammatory properties that might reduce or prevent lung injury. Our hypothesis was that the incidence of PGD could be reduced by a combination of donor lung perfusion and systemic administration of aprotinin to recipients. METHODS AND MATERIALS: The study was randomized and placebo controlled. Donor lungs were perfused during procurement with 4 L Perfadex containing aprotinin (280 mg load + 70 mg/hL) or placebo. Aprotinin or placebo was also administered peri-operatively to the recipients. The study was powered to detect a 10% improvement in the primary endpoint of developing ISHLT grade III PGD anytime within 48 hr following the transplant procedure. RESULTS: There were 48 patients randomized. Diagnosis and the use of bypass were different between groups. The study was stopped prematurely at the planned interim analysis point because of published concerns about renal toxicity of aprotinin. There was no difference in the occurrence of the primary endpoint between groups of patients. The median change from the baseline creatinine level at 24, 48, 72 hr; 7 and 30 d following the transplant was not associated with the administration of aprotinin. CONCLUSIONS: There was no statistically significant difference in the incidence of the primary endpoint between groups in the study. Excess renal failure related to aprotinin administration in a patient population at high risk for the event was not observed.

Human neutrophil peptide in lung chronic allograft dysfunction.

CONTEXT: Our previous case-control study identified human neutrophil peptide (HNP) as a potential biomarker for bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. OBJECTIVE: To prospectively validate HNP as a biomarker for BOS. MATERIALS AND METHODS: HNP was measured by ELISA in bronchoalveolar lavage (BAL) fluid in lung transplant recipients. RESULTS: The first HNP measurement after reaching baseline pulmonary function was predictive of developing BOS ≥2 (p = 0.0419). HNP remained elevated in those that developed BOS. The effect of potential confounders did not significantly impact BOS-free survival time. CONCLUSION: HNP levels are elevated early and persistently in those that develop BOS.

Greater survival despite increased complication rates following lung transplant for alpha-1-antitrypsin deficiency compared to chronic obstructive pulmonary disease.

BACKGROUND: Alpha-1-antitrypsin (A1AT) deficiency (A1ATD) is characterized by accelerated degradation of lung function. We examined our experience with lung transplantation for chronic obstructive pulmonary disease (COPD) with and without A1ATD to compare survival and rates of postoperative surgical complications. METHODS: Patients with A1ATD and non-A1ATD COPD undergoing lung transplantation from 1988-2015 at our institution were analyzed. Complications were categorized into non-gastroenteritis gastrointestinal (GI), wound, airway, and reoperation for bleeding. Overall and complication-free survival were evaluated using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Three hundred and eighty-five patients underwent lung transplant for COPD (98 A1ATD). For A1ATD, 56.1% underwent single lung transplantation (80.6% for COPD). Early overall and complication-free survival was worse for A1ATD, but this trend reversed at longer follow up. Unadjusted estimated survival showed advantage for COPD at 90 days and 1 year, which attenuated by 5 years and reversed at 10 years (P<0.001). On adjusted analysis, A1ATD was associated with a trend toward lower complication-free survival at 90 days and 1 year, due partly to increased rates of post-transplant GI pathology, particularly in the era of the lung allocation score (LAS). CONCLUSIONS: A1ATD lung recipients had worse short-term complication-free survival but improved long-term survival compared to COPD patients. A1ATD was associated with greater risk of new GI pathology after transplant. Close monitoring of A1ATD patients with timely evaluation of GI complaints after transplant is warranted.

Portable normothermic ex-vivo lung perfusion, ventilation, and functional assessment with the Organ Care System on donor lung use for transplantation from extended-criteria donors (EXPAND): a single-arm, pivotal trial.

BACKGROUND: Donor lung use for transplantation is the lowest among solid organ tranplants because of several complex and multifactorial reasons; one area that could have a substantial role is the limited capabilities of cold ischaemic storage. The aim of the EXPAND trial was to evaluate the efficacy of normothermic portable Organ Care System (OCS) Lung perfusion and ventilation on donor lung use from extended-criteria donors and donors after circulatory death, which are rarely used. METHODS: In this single-arm, pivotal trial done in eight institutions across the USA, Germany, and Belgium, lungs from extended-criteria donors were included if fulfilling one or more of the following criteria: a ratio of partial pressure of arterial oxygen (PaO2) to fractional concentration of oxygen inspired air (FiO2) in the donor lung of 300 mm Hg or less; expected ischaemic time longer than 6 h; donor age 55 years or older; or lungs from donors after circulatory death that were recruited and assessed using OCS Lung. Lungs were transplanted if they showed stability of OCS Lung variables, PaO2:FiO2 was more than 300 mm Hg, and they were accepted by the transplanting surgeon. Patients were adult bilateral lung transplant recipients. The primary efficacy endpoint was a composite of patient survival at day 30 post-transplant and absence of The International Society for Heart & Lung Tranplantation primary-graft dysfunction grade 3 (PGD3) within 72 h post-transplantation, with a prespecified objective performance goal of 65%. The primary analysis population was all transplanted recipients. This trial is registered with ClinicalTrials.gov, number NCT01963780, and is now complete. FINDINGS: Between Jan 23, 2014, and Oct 23, 2016, 93 lung pairs were perfused, ventilated, and assessed on the OCS Lung. 12 lungs did not meet OCS transplantation criteria so 81 lungs were suitable for transplantation. Two lungs were excluded for logistical reasons, hence 79 (87%) of eligible lungs were transplanted. The primary endpoint was achieved in 43 (54%) of 79 patients and did not meet the objective performance goal. 35 (44%) of 79 patients had PGD3 within the initial 72 h. 78 (99%) of 79 patients had survived at 30 days post-transplant. The mean number of lung graft-related serious adverse events (respiratory failure and major pulmonary-related infection) was 0·3 events per patient (SD 0·5). INTERPRETATION: Despite missing the objective primary endpoint, the portable OCS Lung resulted in 87% donor lung use for transplantation with excellent clinical outcomes. Many lungs declined by other transplant centres were successfully transplanted using this new technology, which implies its use has the potential to increase the number of lung transplants performed worldwide. Whether similar outcomes could be obtained if these lungs were preserved on ice is unknown and remains an area for future research. FUNDING: TransMedics Inc.

Donation after circulatory death in lung transplantation-five-year follow-up from ISHLT Registry.

BACKGROUND: This study aimed to examine intermediate-term outcomes of lung transplantation (LTx) recipients from donors after circulatory death (DCD). METHODS: We examined the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry data for patients transplanted between January 2003 and June 2017 at 22 centers in North America, Europe, and Australia participating in the DCD Registry. The distribution of continuous variables was summarized as median and interquartile range (IQR) values. Wilcoxon rank sum test was used to compare distribution of continuous variables and chi-square or Fisher's exact test for categorical variables. Kaplan-Meier survival rates after LTx from January 2003 to June 2016 were compared between DCD-III (Maastricht category III withdrawal of life-sustaining therapy [WLST]) only and donors after brain death (DBD) using the log-rank test. Risk factors for 5-year mortality were investigated using Cox multivariate proportional-hazards model. RESULTS: The study cohort included 11,516 lung transplants, of which 1,090 (9.5%) were DCD lung transplants with complete data. DCD-III comprised 94.1% of the DCD cohort. Among the participating centers, the proportion of DCD-LTx performed each year increased from 0.6% in 2003 to 13.5% in 2016. DCD donor management included extubation in 91%, intravenous heparin in 53% and pre-transplant normothermic ex vivo donor lung perfusion in 15%. The median time interval from WLST to cardiac arrest was 15 minutes (IQR: 11-22 minutes) and to cold flush 32 minutes (IQR: 26-41minutes). Compared with DBD, donor age was higher in DCD-III donors (46 years [IQR: 34-55] vs 40 years [IQR: 24-52]), bilateral LTx was performed more often (88.3% vs 76.6%), and more recipients had chronic obstructive pulmonary disease and emphysema as their transplant indication. Five-year survival rates were comparable (63% vs 61%, p = 0.72). In multivariable analysis, recipient and donor ages, indication diagnosis, procedure type (single vs bilateral and double LTx), and transplant era (2003-2009 vs 2010-2016) were independently associated with survival (p < 0.001), but donor type was not (DCD-III vs DBD; hazard ratio, 1.04 [0.90-1.19], p = 0.61). CONCLUSION: This ISHLT DCD Registry report with 5-year follow-up demonstrated similar favorable long-term survival in DCD-III and DBD lung donor recipients at 22 experienced centers globally. These data indicate that more extensive use of DCD-LTx would increase donor organ availability and may reduce waiting list mortality.

Bronchoalveolar lavage cell gene expression in acute lung rejection: development of a diagnostic classifier.

BACKGROUND: Acute lung rejection is a risk factor for chronic rejection, which jeopardizes long-term recipient survival. Presently, acute rejection is diagnosed with the use of transbronchial lung biopsies, which are invasive, expensive, and subject to sampling error. We seek to improve acute rejection diagnostics by identifying genes whose expression in bronchoalveolar lavage (BAL) cells best classifies acute rejection versus no rejection. METHODS: BAL samples were analyzed from 32 subjects whose concurrent histology showed acute rejection (n=14) or no rejection (n=18). Gene expression was measured with Affymetrix microarrays. Quantitative real-time polymerase chain reaction confirmed the microarray results for selected genes. The nearest shrunken centroid method with 10-fold cross validation defined the classification model. A total of 250 iterations of the algorithm were performed to determine the misclassification error rate and the most influential genes in determining classifiers. RESULTS: The estimated overall misclassification rate was <20%. Seven transcripts were present in every classifier, and 52 transcripts were present in >70% of classifiers; these transcripts are related to T-cell function, cytotoxic CD8 activity, and granulocyte degranulation. Eleven of the 52 genes were analyzed with quantitative real-time polymerase chain reaction; all were found to significantly different between the groups, with 10 of 11 increased in acute rejection samples. The proportions of lymphocytes and neutrophils in BAL samples increased in acute rejection but did not outperform the gene-based classifier. CONCLUSIONS: There is a prominent acute rejection-associated signature in BAL cells characterized by increased T-cell, CD8 cytotoxic cell, and neutrophil gene expression. These findings lay the foundation for development of rapid PCR-based assays of gene expression for clinical acute rejection diagnosis.

Early Trends in PaO(2)/fraction of inspired oxygen ratio predict outcome in lung transplant recipients with severe primary graft dysfunction.

BACKGROUND: The development of severe primary graft dysfunction (PGD) is a risk factor for perioperative death following lung transplantation. Our goal is to improve the predictive value of the earliest Pao(2)/fraction of inspired oxygen (P/F) measurements that gauge PGD severity. METHODS: We identified 96 patients with severe PGD (P/F < 200) at ICU arrival through a retrospective review of 431 lung transplants performed at our institution from 1992 to 2005. The P/F trend, represented as quartiles of the 12-h percentage change in P/F, was analyzed using multivariate logistic regression. Study outcomes were 90-day death and long-term survival. RESULTS: The median percentage change in P/F over 12 h was + 52% (interquartile range, +20 to 90%). We observed the highest early mortality among those in the lowest quartile of the P/F trend (an increase in P/F

Pulmonary Transplant Salvage Using Ultrasound-Assisted Thrombolysis of Subacute Occlusive Main Pulmonary Artery Embolus.

A 53-year-old woman who underwent bilateral lung transplantation 14 months before presented with 2 to 3 weeks of severe exertional dyspnea. Workup revealed a complete embolic occlusion of her left main pulmonary artery related to a femoral deep venous thrombosis. The occlusion did not respond to systemic anticoagulation, and a trial of catheter-directed thrombolysis was pursued. Flow to the left lower lobe was restored after 2 days of thromobolytic therapy. The patient is alive and well at more than 1 year of follow-up.

Clinical implications of donor age: A single-institution analysis spanning 3 decades.

BACKGROUND: We sought to clarify the effect of donor age as a continuous variable on morbidity and mortality in a single-institution experience. METHODS: From 1986 to 2016, 882 adult lung transplants were performed, including 396 in the lung allocation score era. Kaplan-Meier curves and Cox proportional hazards models were used to evaluate the association of donor age with overall survival and bronchiolitis obliterans syndrome (BOS) score ≥1-free survival. Logistic regression was used to evaluate the association with primary graft dysfunction grade 3. Natural cubic splines were used to explore donor age in a continuous fashion to allow for nonlinear relationships. RESULTS: In the lung allocation score era, unadjusted 5-year survival was not significantly different between 3 a priori-defined donor age groups: age <40, 40 to 54, and age ≥55 years (64%, 61%, and 69%, P = .8). Unadjusted 5-year freedom from BOS ≥1 was not significantly different (34%, 20%, and 33%, respectively, P = .1). After we adjusted for comorbidities, cubic spline analysis demonstrated no effect between donor age as a continuous variable and hazard for mortality at 5 years. Similarly, no interaction was seen between donor age and risk of BOS or primary graft dysfunction 3. Adjusted analysis of all 882 transplants pre- and postinception of the lung allocation score also showed no effect of age on 10-year survival. CONCLUSIONS: Long-term survival of lung transplant recipients was not affected by the age of the donor. These findings support the notion that donor age could be relaxed.

Colon and rectal complications after heart and lung transplantation.

BACKGROUND: 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. STUDY DESIGN: 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. RESULTS: 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%). CONCLUSIONS: 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.

Allograft rejection after lung transplantation.

Lung transplantation has become an accepted therapy for selected patients with advanced lung disease. One of the main limitations to successful lung transplantation is rejection of the transplanted organ. This article discusses the clinical presentation, treatment, and prevention of hyperacute, acute, and chronic rejection in the lung transplant recipient.