Lung transplantation (LUTX) is often complicated by primary graft dysfunction (PGD). Plasma biomarkers hold potential for PGD phenotyping and targeted therapy. This scoping review aims to collect the available literature in search of serum biomarkers for PGD phenotyping.

Following JBI and PRISMA guidelines, we conducted a systematic review searching MEDLINE, Web of Science, EMBASE and The Cochrane Library for papers reporting the association between serum biomarkers measured within 72 h of reperfusion and PGD, following International Society for Heart and Lung Transplantation (ISHLT) guidelines. We extracted study details, patient demographics, PGD definition and timing, biomarker concentration, and their performance in identifying PGD cases.

Among the 1050 papers screened, 25 prospective observational studies were included, with only nine conducted in the last decade. These papers included 1793 unique adult patients (1195 double LUTX, median study size 100 (IQR 44-119)). Most (n=21) compared PGD grade 3 to less severe PGD, but only four adhered to 2016 PGD definitions. Enzyme-linked immunosorbent assays and the multiplex bead array technique were utilised in 23 and two papers, respectively. In total, 26 candidate biomarkers were identified, comprising 13 inflammatory, three endothelial activation, three epithelial injury, three cellular damage and two coagulation dysregulation markers. Only five biomarkers (sRAGE, ICAM-1, PAI-1, SP-D, FSTL-1) underwent area under the receiver operating characteristic curve analysis, yielding a median value of 0.58 (0.51-0.78) in 406 patients (276 double LUTX).

Several biomarkers exhibit promise for future studies aimed at PGD phenotyping after LUTX. To uncover the significant existing knowledge gaps, further international prospective studies incorporating updated diagnostic criteria, modern platforms and advanced statistical approaches are essential.

Invasive graft biopsies assess the efficacy of immunosuppression through lagging indicators of transplant rejection. We report on a microporous scaffold implant as a minimally invasive immunological niche to assay rejection before graft injury. Adoptive transfer of T cells into Rag2-/- mice with mismatched allografts induced acute cellular allograft rejection (ACAR), with subsequent validation in wild-type animals. Following murine heart or skin transplantation, scaffold implants accumulate predominantly innate immune cells. The scaffold enables frequent biopsy, and gene expression analyses identified biomarkers of ACAR before clinical signs of graft injury. This gene signature distinguishes ACAR and immunodeficient respiratory infection before injury onset, indicating the specificity of the biomarkers to differentiate ACAR from other inflammatory insult. Overall, this implantable scaffold enables remote evaluation of the early risk of rejection, which could potentially be used to reduce the frequency of routine graft biopsy, reduce toxicities by personalizing immunosuppression, and prolong transplant life.

The association between interleukin-1β (IL-1β) concentrations during ex vivo lung perfusion (EVLP) with donor organ quality and post-lung transplant outcome has been demonstrated in several studies. The mechanism underlying IL-1β-mediated donor lung injury was investigated using a paired single-lung EVLP model.

Human lung pairs were dissected into individual lungs and perfused on identical separate EVLP circuits, with one lung from each pair receiving a bolus of IL-1β. Fluorescently labeled human neutrophils isolated from a healthy volunteer were infused into both circuits and quantified in perfusate at regular timepoints. Perfusates and tissues were subsequently analyzed, with perfusates also used in functional assays.

Neutrophil numbers were significantly lower in perfusate samples collected from the IL-1β-stimulated lungs consistent with increased neutrophil adhesion ( P = 0.042). Stimulated lungs gained significantly more weight than controls ( P = 0.046), which correlated with soluble intercellular adhesion molecule-1 (R 2 = 0.71, P = 0.0043) and von-Willebrand factor (R 2 = 0.39, P = 0.040) in perfusate. RNA expression patterns for inflammatory genes were differentially regulated via IL-1β. Blockade of IL-1β significantly reduced neutrophil adhesion in vitro ( P = 0.025).

These data illustrate the proinflammatory functions of IL-1β in the context of EVLP, suggesting this pathway may be susceptible to therapeutic modulation before transplantation.

The comorbidity of pulmonary fibrosis and COPD/emphysema has garnered increasing attention. However, no bibliometric analysis of this comorbidity has been conducted thus far. This study aims to perform a bibliometric analysis to explore the current status and cutting-edge trends in the field, and to establish new directions for future research.

Statistical computing, graphics, and data visualization tools such as VOSviewer, CiteSpace, Biblimatrix, and WPS Office were employed.

We identified a total of 1827 original articles and reviews on the comorbidity of pulmonary fibrosis and COPD/emphysema published between 2004 and 2023. There was an observed increasing trend in publications related to this comorbidity. The United States, Japan, and the United Kingdom were the countries with the highest contributions. Professor Athol Wells and the University of Groningen had the highest h-index and the most articles, respectively. Through cluster analysis of co-cited documents, we identified the top 17 major clusters. Keyword analysis predicted that NF-κB, oxidative stress, physical activity, and air pollution might be hot spots in this field in the future.

This bibliometric analysis demonstrates a continuous increasing trend in literature related to the comorbidity of pulmonary fibrosis and COPD/emphysema. The research hotspots and trends identified in this study provide a reference for in-depth research in this field, aiming to promote the development of the comorbidity of pulmonary fibrosis and COPD/emphysema.

Lung transplantation is the treatment of choice for patients with end-stage lung disease. Currently, just under 5000 lung transplants are performed worldwide annually. However, a major scourge leading to 90-d and 1-year mortality remains primary graft dysfunction. It is a spectrum of lung injury ranging from mild to severe depending on the level of hypoxaemia and lung injury post-transplant. This review aims to provide an in-depth analysis of the epidemiology, patho physiology, risk factors, outcomes, and future frontiers involved in mitigating primary graft dysfunction. The current diagnostic criteria are examined alongside changes from the previous definition. We also highlight the issues surrounding chronic lung allograft dysfunction and identify the novel therapies available for ex-vivo lung perfusion. Although primary graft dysfunction remains a significant contributor to 90-d and 1-year mortality, ongoing research and development abreast with current technological advancements have shed some light on the issue in pursuit of future diagnostic and therapeutic tools.

In lung transplantation, postoperative outcomes favor intraoperative use of extracorporeal membrane oxygenation (ECMO) over cardiopulmonary bypass (CBP). We investigated the effect of intraoperative support strategies on endothelial injury biomarkers and short-term posttransplant outcomes. Adults undergoing bilateral lung transplantation with No-Support, venoarterial (V-A) ECMO, or CPB were included. Plasma samples pre- and post-transplant were collected for Luminex assay to measure endothelial injury biomarkers including syndecan-1 (SYN-1), intercellular adhesion molecule-1 (ICAM-1), and matrix metalloprotease-9. Fifty five patients were included for analysis. The plasma level of SYN-1 at arrival in the intensive care unit was significantly higher with CPB compared to V-A ECMO and No-Support (P < 0.01). The rate of primary graft dysfunction grade 3 (PGD3) at 72 hours was 60.0% in CPB, 40.1% in V-A ECMO, and 15% in No-Support (P = 0.01). Postoperative plasma levels of SYN-1 and ICAM-1 were significantly higher in recipients who developed PGD3 at 72 hours. SYN-1 levels were also significantly higher in patients who developed acute kidney injury and hepatic dysfunction after transplant. Postoperative, SYN-1 upon intensive care arrival was found to be a significant predictive biomarker of PGD3, acute kidney injury, and hepatic dysfunction following lung transplantation. CPB is associated with higher plasma concentrations of SYN-1, a marker of endothelial glycocalyx degradation, upon arrival to the intensive care unit. Higher levels of SYN-1 are predictive of end-organ dysfunction following lung transplantation. Our data suggests that intraoperative strategies aimed at modulating endothelial injury will help improve lung transplantation outcomes.

Many advances in lung transplant have occurred over the last few decades in the understanding of primary graft dysfunction (PGD) though effective prevention and treatment remain elusive. This review will cover prior understanding of PGD, recent findings, and directions for future research. A consensus statement updating the definition of PGD in 2016 highlights the growing complexity of lung transplant perioperative care taking into account the increasing use of high flow oxygen delivery and pulmonary vasodilators in the current era. PGD, particularly more severe grades, is associated with worse short- and long-term outcomes after transplant such as chronic lung allograft dysfunction. Growing experience have helped identify recipient, donor, and intraoperative risk factors for PGD. Understanding the pathophysiology of PGD has advanced with increasing knowledge of the role of innate immune response, humoral cell immunity, and epithelial cell injury. Supportive care post-transplant with technological advances in extracorporeal membranous oxygenation (ECMO) remain the mainstay of treatment for severe PGD. Future directions include the evolving utility of ex vivo lung perfusion (EVLP) both in PGD research and potential pre-transplant treatment applications. PGD remains an important outcome in lung transplant and the future holds a lot of potential for improvement in understanding its pathophysiology as well as development of preventative therapies and treatment.

Prior studies of post-lung transplant acute kidney injury (AKI) have not accounted for confounding effects of primary graft dysfunction (PGD). We sought to test the impact of PGD on AKI risk factors and on the association of AKI with mortality.

We included patients transplanted at the University of Pennsylvania from 2005-12, defined AKI using consensus criteria during transplant hospitalization, and defined PGD as grade 3 at 48-72 hours. We used multivariable logistic regression to test the impact of PGD on AKI risk factors and Cox models to test association of AKI with one-year mortality adjusting for PGD and other confounders.

Of 299 patients, 188 (62.9%) developed AKI with 142 (75%) cases occurring by postoperative day 4. In multivariable models, PGD was strongly associated with AKI (OR 3.76, 95% CI 1.72-8.19, P = .001) but minimally changed associations of other risk factors with AKI. Both AKI (HR 3.64, 95% CI 1.68-7.88, P = .001) and PGD (HR 2.55, 95% CI 1.40-4.64, P = .002) were independently associated with one-year mortality.

Post-lung transplant AKI risk factors and association of AKI with mortality were independent of PGD. AKI may therefore be a target for improving lung transplant mortality rather than simply an epiphenomenon of PGD.

Primary graft dysfunction (PGD) is a major limitation in short- and long-term lung transplant survival. Recent work has shown that mitochondrial damage-associated molecular patterns (mtDAMPs) can promote solid organ injury, but whether they contribute to PGD severity remains unclear. We quantitated circulating plasma mitochondrial DNA (mtDNA) in 62 patients, before lung transplantation and shortly after arrival to the intensive care unit. Although all recipients released mtDNA, high levels were associated with severe PGD development. In a mouse orthotopic lung transplant model of PGD, we detected airway cell-free damaged mitochondria and mtDNA in the peripheral circulation. Pharmacologic inhibition or genetic deletion of formylated peptide receptor 1 (FPR1), a chemotaxis sensor for N-formylated peptides released by damaged mitochondria, inhibited graft injury. An analysis of intragraft neutrophil-trafficking patterns reveals that FPR1 enhances neutrophil transepithelial migration and retention within airways but does not control extravasation. Using donor lungs that express a mitochondria-targeted reporter protein, we also show that FPR1-mediated neutrophil trafficking is coupled with the engulfment of damaged mitochondria, which in turn triggers reactive oxygen species (ROS)-induced pulmonary edema. Therefore, our data demonstrate an association between mtDAMP release and PGD development and suggest that neutrophil trafficking and effector responses to damaged mitochondria are drivers of graft damage.

Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved, and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted.

We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity.

Data from the Lung Transplant Outcomes Group multicenter cohort were used to compare variations on the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination.

A total of 1,179 subjects from 10 centers were enrolled from 2007 to 2012. Median length of follow-up was 4 years (interquartile range = 2.4-5.9). No mortality differences were noted between no PGD (grade 0) and mild PGD (grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48-72 hours; P < 0.001). Biomarker divergent discrimination was superior when collapsing grades 0 and 1. Additional severity grades, use of mechanical ventilation, and transplant procedure type had minimal or no effect on mortality or biomarker discrimination.

The PGD consensus definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination.

The transfusion-related respiratory complications, transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO), are leading causes of transfusion-related morbidity and mortality. At present, there are no effective preventive strategies with red blood cell (RBC) transfusion. Although mechanisms remain incompletely defined, soluble biological response modifiers (BRMs) within the RBC storage solution may play an important role. Point-of-care (POC) washing of allogeneic RBCs may remove these BRMs, thereby mitigating their impact on post-transfusion respiratory complications.

This is a multicenter randomised clinical trial of standard allogeneic versus washed allogeneic RBC transfusion for adult patients undergoing cardiac surgery testing the hypothesis that POC RBC washing is feasible, safe, and efficacious and will reduce recipient immune and physiologic responses associated with transfusion-related respiratory complications. Relevant clinical outcomes will also be assessed. This investigation will enrol 170 patients at two hospitals in the USA. Simon's two-stage design will be used to assess the feasibility of POC RBC washing. The primary safety outcomes will be assessed using Wilcoxon Rank-Sum tests for continuous variables and Pearson chi-square test for categorical variables. Standard mixed modelling practices will be employed to test for changes in biomarkers of lung injury following transfusion. Linear regression will assess relationships between randomised group and post-transfusion physiologic measures.

Safety oversight will be conducted under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained by the DSMB as well as the institutional review boards at each institution prior to enrolling the first study participant. This study aims to provide important information regarding the feasibility of POC washing of allogeneic RBCs and its potential impact on ameliorating post-transfusion respiratory complications. Additionally, it will inform the feasibility and scientific merit of pursuing a more definitive phase II/III clinical trial.

ClinicalTrials.gov registration number is NCT02094118 (Pre-results).

After lung transplantation (LT), early prediction of grade 3 pulmonary graft dysfunction (PGD) remains a research gap for clinicians. We hypothesized that it could be improved using extravascular lung water (EVLWi) and plasma biomarkers of acute lung injury.

After institutional review board approval and informed consent, consecutive LT recipients were included. Transpulmonary thermodilution-based EVLWi, plasma concentrations of epithelial (soluble receptor for advanced glycation endproducts [sRAGE]) and endothelial biomarkers (soluble intercellular adhesion molecule-1 and endocan [full-length and cleaved p14 fragment]) were obtained before and after LT (0 [H0], 6, 12, 24, 48 and 72 hours after pulmonary artery unclamping). Grade 3 PGD was defined according to the International Society for Lung and Heart Transplantation definition, combining arterial oxygen partial pressure (PaO2)/inspired fraction of oxygen (FiO2) ratio and chest X-rays. Association of clinical risk factors, EVLWi and biomarkers with grade 3 PGD was analyzed under the Bayesian paradigm, using logistic model and areas under the receiver operating characteristic curves (AUCs).

In 47 LT recipients, 10 developed grade 3 PGD, which was obvious at H6 in 8 cases. Clinical risk factors, soluble intercellular adhesion molecule-1 and endocan (both forms) were not associated with grade 3 PGD. Significant predictors of grade 3 PGD included (1) EVLWi (optimal cutoff, 13.7 mL/kg; AUC, 0.74; 95% confidence interval [CI], 0.48-0.99), (2) PaO2/FiO2 ratio (optimal cutoff, 236; AUC, 0.68; 95% CI, 0.52-0.84), and (3) sRAGE (optimal cutoff, 11 760 pg/mL; AUC, 0.66; 95% CI, 0.41-0.91) measured at H0.

Immediate postreperfusion increases in EVLWi and sRAGE along with impaired PaO2/FiO2 ratios were early predictors of grade 3 PGD at or beyond 6 hours and may trigger early therapeutic interventions.

Ex vivo lung perfusion (EVLP) enables assessment of marginal donor lungs for transplantation. We aimed to discover biomarkers in EVLP perfusate that could predict development of primary graft dysfunction (PGD). From September 2008 to August 2013, 100 clinical EVLPs were performed. Eleven patients developed PGD grade 3 within 72 h after transplant. The non-PGD group consisted of 34 patients without PGD grade 3. Nonbilateral lung transplants or transplant after extracorporeal life support were excluded from analyses. Soluble intercellular adhesion molecule 1 (sICAM-1), soluble VCAM-1 (sVCAM-1), and soluble E selectin (sE-selectin) levels, as markers of endothelial activation, were measured in the perfusate of EVLP by enzyme-linked immunosorbent assay and were correlated with clinical outcome. Levels of sICAM-1 at 1 h and sVCAM-1 at 1 and 4 h were significantly higher in the PGD group compared with the non-PGD group. The sE selectin levels were not statistically different between the study groups. Higher levels of sVCAM-1 at 1 and 4 h were statistically significantly associated with PGD either alone or after adjustment for other PGD risk factors. These adhesion molecules may help identify donor lungs at higher risk of PGD during EVLP.

Severe primary graft dysfunction affects 15-20% of lung transplant recipients and carries a high mortality risk. In addition to known donor, recipient, and perioperative clinical risk factors, numerous biologic factors are thought to contribute to primary graft dysfunction. Our current understanding of the pathogenesis of lung injury and primary graft dysfunction emphasizes multiple pathways leading to lung endothelial and epithelial injury. Protein biomarkers specific to these pathways can be measured in the plasma, bronchoalveolar lavage fluid, and lung tissue. Clarification of the pathophysiology and timing of primary graft dysfunction could illuminate predictors of dysfunction, allowing for better risk stratification, earlier identification of susceptible recipients, and development of targeted therapies. Here, we review much of what has been learned about the association of protein biomarkers with primary graft dysfunction and evaluate this association at different measurement time points.

Lungs stored ahead of transplant surgery experience ischemia. Pulmonary ischemia differs from ischemia in the systemic organs in that stop of blood flow in the lung leads to loss of shear alone because the lung parenchyma does not rely on blood flow for its cellular oxygen requirements. Our earlier studies on the ischemia-induced mechanosignaling cascade showed that the pulmonary endothelium responds to stop of flow by production of reactive oxygen species (ROS). We hypothesized that ROS produced in this way led to induction of proinflammatory mediators. In this study, we used lungs or cells subjected to various periods of storage and evaluated the induction of several proinflammatory mediators. Isolated murine, porcine and human lungs in situ showed increased expression of cellular adhesion molecules; the damage-associated molecular pattern protein high-mobility group box 1 and the corresponding pattern recognition receptor, called the receptor for advanced glycation end products; and induction stabilization and translocation of hypoxia-inducible factor 1α and its downstream effector VEGFA, all of which are participants in inflammation. We concluded that signaling with lung preservation drives expression of inflammatory mediators that potentially predispose the donor lung to an inflammatory response after transplant.

Lung transplantation is the treatment of choice for end-stage pulmonary diseases. In order to avoid or reduce pulmonary and systemic complications, mechanical ventilator settings have an important role in each stage of lung transplantation. In this respect, the use of mechanical ventilation with a tidal volume of 6 to 8 ml  kg(-1) predicted body weight, positive end-expiratory pressure of 6 to 8 cmH2O and a plateau pressure lower than 30 cmH2O has been suggested for the donor during surgery, and for the recipient both during and after surgery. For the present review, we systematically searched the PubMed database for articles published from 2000 to 2014 using the following keywords: lung transplantation, protective mechanical ventilation, lung donor, extracorporeal membrane oxygenation, recruitment manoeuvres, extracorporeal CO2 removal and noninvasive ventilation.

We hypothesized that administration of a homodimer of recombinant annexin V, diannexin, could shield phosphatidylserine on the endothelium, and inhibit leukocyte and platelet adhesion, thereby potentially reducing ischemia reperfusion injury (IRI) in lung transplantation. This hypothesis was tested using a rat syngeneic single left-lung transplant model.

Rats were randomly assigned to receive diannexin (DN group; n = 10) or normal saline (control group; n = 10). Diannexin (1000 μg/kg) was administered to the donor lung in the pulmonary flush solution, and to the recipient intravenously, 5 minutes after initiation of reperfusion. Grafts were reperfused for 2 hours.

The transplanted grafts in the DN group performed significantly better in gas exchange with higher partial pressure of oxygen (control group: 179 ± 121 vs DN group: 330 ± 54 mm Hg; P = .007) and lower partial pressure of carbon dioxide (control: 55.1 ± 26 vs DN: 34.2 ± 11 mm Hg; P = .04), as well as lower peak airway pressure (control: 20.5 ± 8.5 vs DN: 12.0 ± 7.9 cm H2O; P = .035) after 2 hours of reperfusion. Wet-to-dry lung weight ratio (P = .054), and alveolar fibrin deposition score (P = .04), were reduced in the DN group. Caspase-cleaved cytokeratin 18 in plasma (a marker of epithelial apoptosis) was significantly reduced in the DN group (P = .013). Furthermore, gene-expression levels of proinflammatory cytokines in the transplanted graft, including interleukin-6 (P = .04) and macrophage inflammatory protein 2 (P = .03) were significantly decreased in the DN group.

A homodimer of recombinant annexin V reduced ischemia reperfusion injury in a lung transplant animal model, by reducing cell death and tissue inflammation.

Primary graft dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in the Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002 to 2010; with separate validation in 382 subjects accrued from 2011 to 2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 h, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed three prediction models, where low-risk recipients had a normal BMI (18.5-25 kg/m(2) ), chronic obstructive pulmonary disease/cystic fibrosis, and absent or mild pulmonary hypertension (mPAP<40 mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4-7%, and high-risk a predicted PGD risk of 15-18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5% and 25%. We conclude that valid estimates of PGD risk can be produced using readily available clinical variables.

Primary graft dysfunction (PGD) remains a significant cause of lung transplant postoperative morbidity and mortality. The underlying mechanisms of PGD development are not completely understood. This study analyzed the effect of right ventricular function (RVF) on PGD development.

A retrospective analysis of a prospectively assessed cohort was performed at a single institution between July 2010 and June 2013. The primary outcome was development of PGD grade 3 (PGD3). Conventional echocardiographic parameters and speckle-tracking echocardiography, performed during the pre-transplant evaluation phase up to 1 year before surgery, were used to assess preoperative RVF.

Included were 120 lung transplant recipients (LTr). Systolic pulmonary arterial pressure (48 ± 20 vs 41 ± 18 mm Hg; p = 0.048) and ischemia time (349 ± 73 vs 306 ± 92 minutes; p < 0.01) were higher in LTr who developed PGD3. Patients who developed PGD3 had better RVF estimated by basal free wall longitudinal strain (BLS; -24% ± 9% vs -20% ± 6%; p = 0.039) but had a longer intensive care unit length of stay and mechanical ventilation and higher 6-month mortality. BLS ≥ -21.5% was the cutoff that best identified patients developing PGD3 (area under the receiver operating characteristic curve, 0.70; 95% confidence interval, 0.54-0.85; p = 0.020). In the multivariate analysis, a BLS ≥ -21.5% was an independent risk factor for PGD3 development (odds ratio, 4.56; 95% confidence interval, 1.20-17.38; p = 0.026), even after adjusting for potential confounding.

A better RVF, as measured by BLS, is a risk factor for severe PGD. Careful preoperative RVF assessment using speckle-tracking echocardiography may identify LTrs with the highest risk of developing PGD.

Oxidant stress pathway activation during ischemia reperfusion injury may contribute to the development of primary graft dysfunction (PGD) after lung transplantation. We hypothesized that oxidant stress gene variation in recipients and donors is associated with PGD.

Donors and recipients from the Lung Transplant Outcomes Group (LTOG) cohort were genotyped using the Illumina IBC chip filtered for oxidant stress pathway genes. Single nucleotide polymorphisms (SNPs) grouped into SNP sets based on haplotype blocks within 49 oxidant stress genes selected from gene ontology pathways and literature review were tested for PGD association using a sequencing kernel association test. Analyses were adjusted for clinical confounding variables and population stratification.

Three hundred ninety-two donors and 1038 recipients met genetic quality control standards. Thirty percent of patients developed grade 3 PGD within 72 hours. Donor NADPH oxidase 3 (NOX3) was associated with PGD (P = .01) with 5 individual significant loci (P values between .006 and .03). In recipients, variation in glutathione peroxidase (GPX1) and NRF-2 (NFE2L2) was significantly associated with PGD (P = .01 for both). The GPX1 association included 3 individual loci (P values between .006 and .049) and the NFE2L2 association included 2 loci (P = .03 and .05). Significant epistatic effects influencing PGD susceptibility were evident between 3 different donor blocks of NOX3 and recipient NFE2L2 (P = .026, P = .017, and P = .031).

Our study has prioritized GPX1, NOX3, and NFE2L2 genes for future research in PGD pathogenesis, and highlights a donor-recipient interaction of NOX3 and NFE2L2 that increases the risk of PGD.

Optimal ventilator management for patients with acute respiratory distress syndrome (ARDS) remains uncertain. Lower tidal volume ventilation appears to be beneficial, but optimal management of positive end-expiratory pressure (PEEP) remains unclear. The Esophageal Pressure-Guided Ventilation 2 Trial (EPVent2) aims to examine the impact of mechanical ventilation directed at maintaining a positive transpulmonary pressure (PTP) in patients with moderate-to-severe ARDS.

EPVent2 is a multicentre, prospective, randomised, phase II clinical trial testing the hypothesis that the use of a PTP-guided ventilation strategy will lead to improvement in composite outcomes of mortality and time off the ventilator at 28 days as compared with a high-PEEP control. This study will enrol 200 study participants from 11 hospitals across North America. The trial will utilise a primary composite end point that incorporates death and days off the ventilator at 28 days to test the primary hypothesis that adjusting ventilator pressure to achieve positive PTP values will result in improved mortality and ventilator-free days.

Safety oversight will be under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained from the DSMB prior to enrolling the first study participant. Approvals of the protocol as well as informed consent documents were also obtained from the Institutional Review Board of each participating institution prior to enrolling study participants at each respective site. The findings of this investigation, as well as associated ancillary studies, will be disseminated in the form of oral and abstract presentations at major national and international medical specialty meetings. The primary objective and other significant findings will also be presented in manuscript form. All final, published manuscripts resulting from this protocol will be submitted to PubMed Central in accordance with the National Institute of Health Public Access Policy.

ClinicalTrials.gov under number NCT01681225.

Biologic pathways with significant genetic conservation across human populations have been implicated in the pathogenesis of primary graft dysfunction (PGD). The evaluation of the role of recipient genetic variation in PGD has thus far been limited to single, candidate gene analyses.

We sought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a two-phase large-scale genotyping approach.

Phase 1 was a large-scale candidate gene association study of the multicenter, prospective Lung Transplant Outcomes Group cohort. Phase 2 included functional evaluation of selected variants and a bioinformatics screening of variants identified in phase 1.

After genetic data quality control, 680 lung transplant recipients were included in the analysis. In phase 1, a total of 17 variants were significantly associated with PGD, four of which were in the prostaglandin E2 family of genes. Among these were a coding variant in the gene encoding prostaglandin E2 synthase (PTGES2; P = 9.3 × 10(-5)) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 5' promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4; all P < 5 × 10(-5)). Functional evaluation in regulatory T cells identified that rs4434423A in the PTGER4 gene was associated with differential suppressive function of regulatory T cells.

Further research aimed at replication and additional functional insight into the role played by genetic variation in prostaglandin E2 synthetic and signaling pathways in PGD is warranted.

Inherent recipient factors, including pretransplant diagnosis, obesity and elevated pulmonary pressures, are established primary graft dysfunction (PGD) risks. We evaluated the relationship between preoperative lung injury biomarkers and PGD to gain further mechanistic insight in recipients. We performed a prospective cohort study of recipients in the Lung Transplant Outcomes Group enrolled between 2002 and 2010. Our primary outcome was Grade 3 PGD on Day 2 or 3. We measured preoperative plasma levels of five biomarkers (CC-16, sRAGE, ICAM-1, IL-8 and Protein C) that were previously associated with PGD when measured at the postoperative time point. We used multivariable logistic regression to adjust for potential confounders. Of 714 subjects, 130 (18%) developed PGD. Median CC-16 levels were elevated in subjects with PGD (10.1 vs. 6.0, p<0.001). CC-16 was associated with PGD in nonidiopathic pulmonary fibrosis (non-IPF) subjects (OR for highest quartile of CC-16: 2.87, 95% CI: 1.37, 6.00, p=0.005) but not in subjects with IPF (OR 1.38, 95% CI: 0.43, 4.45, p=0.59). After adjustment, preoperative CC-16 levels remained associated with PGD (OR: 3.03, 95% CI: 1.26, 7.30, p=0.013) in non-IPF subjects. Our study suggests the importance of preexisting airway epithelial injury in PGD. Markers of airway epithelial injury may be helpful in pretransplant risk stratification in specific recipients.

There is significant heterogeneity within the primary graft dysfunction (PGD) syndrome. We aimed to identify distinct grade 3 PGD phenotypes based on severity of lung dysfunction and patterns of resolution.

Subjects from the Lung Transplant Outcomes Group (LTOG) cohort study with grade 3 PGD within 72 h after transplantation were included. Latent class analysis (LCA) was used to statistically identify classes based on changes in PGD International Society for Heart & Lung Transplantation grade over time. Construct validity of the classes was assessed by testing for divergence of recipient, donor, and operative characteristics between classes. Predictive validity was assessed using time to death.

Of 1,255 subjects, 361 had grade 3 PGD within the first 72 h after transplantation. LCA identified three distinct phenotypes: (1) severe persistent dysfunction (class 1), (2) complete resolution of dysfunction within 72 h (class 2), and (3) attenuation, without complete resolution within 72 h (class 3). Increased use of cardiopulmonary bypass, greater RBC transfusion, and higher mean pulmonary artery pressure were associated with persistent PGD (class 1). Subjects in class 1 also had the greatest risk of death (hazard ratio, 2.39; 95% CI, 1.57-3.63; P &lt; .001).

There are distinct phenotypes of resolution of dysfunction within the severe PGD syndrome. Subjects with early resolution may represent a different mechanism of lung pathology, such as resolving pulmonary edema, whereas those with persistent PGD may represent a more severe phenotype. Future studies aimed at PGD mechanism or treatment may focus on phenotypes based on resolution of graft dysfunction.

Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction.

Primary graft dysfunction (PGD) is a syndrome encompassing a spectrum of mild to severe lung injury that occurs within the first 72 hours after lung transplantation. PGD is characterized by pulmonary edema with diffuse alveolar damage that manifests clinically as progressive hypoxemia with radiographic pulmonary infiltrates. In recent years, new knowledge has been generated on risks and mechanisms of PGD. Following ischemia and reperfusion, inflammatory and immunological injury-repair responses appear to be key controlling mechanisms. In addition, PGD has a significant impact on short- and long-term outcomes; therefore, the choice of donor organ is impacted by this potential adverse consequence. Improved methods of reducing PGD risk and efforts to safely expand the pool are being developed. Ex vivo lung perfusion is a strategy that may improve risk assessment and become a promising platform to implement treatment interventions to prevent PGD. This review details recent updates in the epidemiology, pathophysiology, molecular and genetic biomarkers, and state-of-the-art technical developments affecting PGD.

The objective of this study was to evaluate the role of autotaxin (ATX) activity and gene expression compared to soluble intercellular adhesion molecule-1 (sICAM-1) in thyroid carcinoma.


Sixty-five patients with thyroid swelling were included. There were 20 cases of simple multinodular goiter (group I), 15 cases of follicular adenoma (group II) and 30 cases of thyroid cancer (group III). Group III was further subdivided into negative and positive lymph nodes (group IIIa and IIIb; 22 and 8 cases, respectively). sICAM-1 concentration and ATX activity were measured using colorimetric enzyme-linked immunosorbent assay (ELISA), while ATX gene expression was detected by real-time polymerase chain reaction (PCR).


sICAM-1 level, ATX activity and gene expression were significantly elevated in patients with thyroid carcinoma compared to other groups. The ATX activity showed significantly higher sensitivity and specificity than sICAM-1 (100% and 97.1% vs 93.3% and 88.6%, respectively). Both sICAM-1 and ATX values were significantly higher in patients with positive lymph nodes compared to those without lymph node involvement (p<0.001). Higher levels of ATX activity and gene expression were significantly correlated with larger tumor size and undifferentiated pathological subtype in thyroid carcinoma. In this respect, ATX was superior to sICAM-1.


Our data suggest that ATX activity and gene expression are reliable diagnostic and prognostic tools in thyroid carcinoma compared to sICAM-1.

Monocyte chemotactic protein-1 (MCP-1), also known as "chemokine ligand 2" (CCL2), is a monocyte-attracting chemokine produced in lung epithelial cells. We previously reported an association of increased levels of plasma MCP-1 with primary graft dysfunction (PGD) after lung transplantation in a nested case-control study of extreme phenotypes using a multiplex platform. In this study, we sought to evaluate the role of plasma MCP-1 level as a biomarker across the full spectrum of PGD. We performed a prospective cohort study of 108 lung transplant recipients within the Lung Transplant Outcomes Group cohort. Plasma MCP-1 levels were measured pretransplantation and 6 and 24 hours after transplantation. The primary outcome was development of grade 3 PGD within 72 hours of transplant, with secondary analyses at the 72-hour time point. Multivariable logistic regression was used to evaluate confounding. Thirty subjects (28%) developed PGD. Median MCP-1 measured at 24 hours post-transplant was elevated in subjects with PGD (167.95 vs 103.5 pg/mL, P = .04). MCP-1 levels at 24 hours were associated with increased odds of grade 3 PGD after lung transplantation (odds ratio for each 100 pg/mL, 1.24; 95% confidence interval, 1.00-1.53) and with grade 3 PGD present at the 72-hour time point (odds ratio for each 100 pg/mL, 1.57; 95% confidence interval, 1.18-2.08), independent of confounding variables in multivariable analyses. MCP-1 levels measured preoperatively and 6 hours after transplant were not significantly associated with PGD. Persistent elevations in MCP-1 levels at 24 hours are a biomarker of grade 3 PGD post-transplantation. Monocyte chemotaxis may play a role in the pathogenesis of PGD.

We aimed to identify combinations of biomarkers to enhance the definition of primary graft dysfunction (PGD) for translational research.

Biomarkers reflecting lung epithelial injury (soluble receptor for advance glycation end products [sRAGE] and surfactant protein-D [SP-D]), coagulation cascade (plasminogen activator inhibitor-1 [PAI-1] and protein C), and cell adhesion (intracellular adhesion molecule-1 [ICAM-1]) were measured in the plasma of 315 individuals derived from the Lung Transplant Outcomes Group cohort at 6 and 24 hours after transplantation. We assessed biomarker utility in 2 ways: first, we tested the discrimination of grade 3 PGD within 72 hours; second, we tested the predictive utility of plasma biomarkers for 90-day mortality.

PGD developed in 86 of 315 individuals (27%). Twenty-patients (8%) died within 90 days of transplantation, of which 16 (70%) had PGD. Biomarkers measured at 24 hours had greater discrimination than at 6 hours. Individually, sRAGE (area under the curve [AUC], 0.71) and PAI-1 (AUC, 0.73) had the best discrimination of PGD. The combinations of sRAGE with PAI-1 (AUC, 0.75), PAI-1 with ICAM-1 (AUC, 0.75), and PAI-1 with SP-D (AUC, 0.76) had the best discrimination. Combinations of greater than 2 biomarkers did not significantly enhance discrimination of PGD. ICAM-1 with PAI-1 (AUC, 0.72) and ICAM-1 with sRAGE (AUC, 0.72) had the best prediction for 90-day mortality. The addition of ICAM-1, PAI-1, or sRAGE to the concurrent clinical PGD grade significantly improved the prediction of 90-day mortality (p < 0.001 each).

Measurement of the combination of a marker of impaired fibrinolysis with an epithelial injury or cell adhesion marker had the best discrimination for PGD and prediction for early death and may provide an alternative outcome useful in future research.

Lung transplantation is a therapeutic option for pulmonary diseases in which the other treatment options have failed or in cases of rapid disease progression. However, transplantation is not free from complications, and primary graft dysfunction is one of them. Primary graft dysfunction is a form of acute lung injury. It characteristically develops during the immediate postoperative period, being associated to high morbidity and mortality, and increased risk of bronchiolitis obliterans. Different terms have been used in reference to primary graft dysfunction, leading to a consensus document to clarify the definition in 2005. This consensus document regards primary graft dysfunction as non-cardiogenic pulmonary edema developing within 72 hours of reperfusion and intrinsically attributable to alteration of the lung parenchyma. A number of studies have attempted to identify risk factors and to establish the underlying physiopathology, with a view to developing potential therapeutic options. Such options include nitric oxide and pulmonary surfactant together with supportive measures such as mechanical ventilation or oxygenation bypass.

Primary graft dysfunction (PGD) frequently complicates lung transplantation in the immediate postoperative period. Both female gender and estradiol modulate the body's response to injury and can influence the rate of alveolar fluid clearance.

We hypothesized that female gender and higher estradiol levels would be associated with a lower risk of PGD after lung transplantation.

We measured plasma estradiol levels preoperatively, 6 hours postoperatively, and 24 hours postoperatively in a cohort of 111 lung transplant recipients at 2 institutions.

Mean age was 57 years (12.5) and 52% were female. Median postoperative estradiol level was 63.9 pg/mL (interquartile range, 28.8-154.3 pg/mL) in male and 65.1 pg/mL (interquartile range, 28.4-217.2 pg/mL) in female patients. Contrary to our hypothesis, higher estradiol levels at 24 hours were associated with an increased risk of PGD at 72 hours in male patients (P = 0.001). This association was preserved when accounting for other factors known to be associated with PGD. However, there was no relationship between gender and risk of PGD or between estradiol levels and PGD in females.

These findings suggest that there might be different biologic effects of estrogens in males and females, and highlight the importance of considering gender differences in future studies of PGD.

Obesity has been linked to acute lung injury and is a risk factor for early mortality after lung transplantation.

To examine the associations of obesity and plasma adipokines with the risk of primary graft dysfunction after lung transplantation.

We performed a prospective cohort study of 512 adult lung transplant recipients with chronic obstructive pulmonary disease or interstitial lung disease enrolled in the Lung Transplant Outcomes Group Study. In a nested case-control study, we measured plasma leptin, adiponectin, and resistin before lung transplantation and 6 and 24 hours after lung transplantation in 40 cases of primary graft dysfunction and 80 control subjects. Generalized linear mixed models and logistic regression were used to estimate risk ratios and odds ratios.

Grade 3 primary graft dysfunction developed within 72 hours of transplantation in 29% participants. Obesity was associated with a twofold increased risk of primary graft dysfunction (adjusted risk ratio 2.1; 95% confidence interval, 1.7-2.6). The risk of primary graft dysfunction increased by 40% (confidence interval, 30–50%) for each 5 kg/m(2) increase in body mass index after accounting for center, diagnosis, cardiopulmonary bypass, and transplant procedure. Higher plasma leptin levels were associated with a greater risk of primary graft dysfunction (sex-adjusted P = 0.02). The associations of both obesity and leptin with primary graft dysfunction tended to be stronger among those who did not undergo cardiopulmonary bypass.

Obesity is an independent risk factor for primary graft dysfunction after lung transplantation.

Acute lung injury (ALI) is a devastating condition that places a heavy burden on public health resources. Although the need for effective ALI prevention strategies is increasingly recognised, no effective preventative strategies exist. The Lung Injury Prevention Study with Aspirin (LIPS-A) aims to test whether aspirin (ASA) could prevent and/or mitigate the development of ALI.

LIPS-A is a multicentre, double-blind, randomised clinical trial testing the hypothesis that the early administration of ASA will result in a reduced incidence of ALI in adult patients at high risk. This investigation will enrol 400 study participants from 14 hospitals across the USA. Conditional logistic regression will be used to test the primary hypothesis that early ASA administration will decrease the incidence of ALI.

Safety oversight will be under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained from the DSMB prior to enrolling the first study participant. Approval of both the protocol and informed consent documents were also obtained from the institutional review board of each participating institution prior to enrolling study participants at the respective site. In addition to providing important clinical and mechanistic information, this investigation will inform the scientific merit and feasibility of a phase III trial on ASA as an ALI prevention agent. The findings of this investigation, as well as associated ancillary studies, will be disseminated in the form of oral and abstract presentations at major national and international medical specialty meetings. The primary objective and other significant findings will also be presented in manuscript form. All final, published manuscripts resulting from this protocol will be submitted to Pub Med Central in accordance with the National Institute of Health Public Access Policy.

Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll-like receptor and IL-1-induced long pentraxin-3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non-PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted.