A randomized controlled trial of presatovir for respiratory syncytial virus after lung transplant.

BACKGROUND: Respiratory syncytial virus (RSV) infection in lung transplant recipients is associated with high morbidity. This study evaluated the RSV fusion inhibitor presatovir in RSV-infected lung transplant recipients. METHODS: In this international Phase 2b, randomized, double-blind, placebo-controlled trial (NCT02534350), adult lung transplant recipients with symptomatic confirmed RSV infection for ≤7 days received oral presatovir 200 mg on day 1 and 100 mg daily on days 2 to 14, or placebo (2:1), with follow-up through day 28. There were 2 coprimary endpoints: time-weighted average change in nasal RSV load from day 1 to 7, calculated from nasal swabs, in the full analysis set ([FAS]; all patients who received study drug and had quantifiable baseline nasal RSV load) and time-weighted average change in nasal RSV load from day 1 to 7 in the subset of patients with pretreatment symptom duration at the median or shorter of the FAS. Secondary endpoints were changes in respiratory infection symptoms assessed using the Influenza Patient-Reported Outcomes questionnaire and lung function measured by spirometry. RESULTS: Sixty-one patients were randomized, 40 received presatovir, 20 placebo, and 54 were included in efficacy analyses. Presatovir did not significantly improve the primary endpoint in the FAS (treatment difference [95% CI], 0.10 [-0.43, 0.63] log10 copies/ml; p = 0.72) or the shorter symptom-duration subgroup (-0.12 [-0.94, 0.69] log10 copies/ml; p = 0.76). Secondary endpoints were not different between presatovir and placebo groups. Presatovir was generally well tolerated. CONCLUSIONS: Presatovir treatment did not significantly improve change in nasal RSV load, symptoms, or lung function in lung transplant recipients.

Lung and liver transplantation in patients with alpha-1 antitrypsin deficiency.

Alpha-1 antitrypsin (AAT) augmentation is effective in slowing the progression of emphysema due to AAT deficiency (AATD) but cannot prevent eventual progression to end-stage lung disease and complete respiratory failure, which is the leading cause of death for individuals with severe AATD. When patients develop end-stage lung disease, lung transplantation is the only treatment option available, and this can improve lung physiology and patient health status. The available data suggest that survival rates for lung transplantation are significantly higher for patients with AATD-related chronic obstructive pulmonary disease (COPD) compared with non-AATD-related COPD, but, conversely, there is a higher risk of common post-lung transplant complications in patients with AATD versus non-AATD COPD. Nevertheless, lung transplantation (single and bilateral) is favorable for patients with AATD. After respiratory failure, the second leading cause of death in patients with AATD is liver disease, for example, cirrhosis and hepatocellular carcinoma, caused by the accumulation of mutant forms of AAT retained within the liver. As with lung disease, the only treatment option for end-stage liver disease is liver transplantation. Survival rates for patients with AATD undergoing liver transplantation are also favorable, and patients, particularly pediatric patients, have benefitted from advancements in peri-/post-surgical care. As the majority of AAT is produced by the liver, the AAT phenotype of the recipient becomes that of the donor, meaning that AAT serum levels should be normalized (if the donor is AAT-replete), halting further lung and liver disease progression. However, post-liver transplant respiratory function may continue to decline in line with normal age-related lung function decline. In the most severe cases, where patients have simultaneous end-stage lung and liver disease, combined lung and liver transplantation is a treatment option with favorable outcomes. However, there is very little information available on this procedure in patients with AATD.

Natural occurrence of Azospirillum brasilense in petunia with capacity to improve plant growth and flowering.

To evaluate the natural occurrence of the plant growth-promoting bacterium Azospirillum brasilense and petunia plants, local strains were isolated and characterized by biochemical and molecular methods. Three strains were assessed in greenhouse conditions using Petunia × hybrida Ultra™. Treatments: Plants without bacterial inoculation or chemical fertilization; fertilized with NPK and KNO3 ; and independently inoculated with the strains 2A1, 2A2, and 2E1 by submerging their roots in a bacterial suspension (~106 CFU·ml-1 ). Root length, dry weight of roots and shoots, leaf area, leaf greenness, and nutrient content were evaluated. The number of days from transplanting to the opening of the first flower and the number of flowers per plant were also determined. As a result, five isolates were characterized as A. brasilense, showing the capacity to produce indoles and siderophores, to solubilize phosphate, nitrogenase activity, and nifH-PCR amplification. In general, all the parameters of the plant assay were improved in plants inoculated with A. brasilense, with variations among the strains, as well as the onset of flowering and the number of flowers per plant, compared with uninoculated or fertilized plants. This is the first report on the natural occurrence of A. brasilense in petunia with the capacity to improve plant growth and flowering.

Nanostructures in Hydrogen Peroxide Sensing.

In recent years, several devices have been developed for the direct measurement of hydrogen peroxide (H2O2), a key compound in biological processes and an important chemical reagent in industrial applications. Classical enzymatic biosensors for H2O2 have been recently outclassed by electrochemical sensors that take advantage of material properties in the nano range. Electrodes with metal nanoparticles (NPs) such as Pt, Au, Pd and Ag have been widely used, often in combination with organic and inorganic molecules to improve the sensing capabilities. In this review, we present an overview of nanomaterials, molecules, polymers, and transduction methods used in the optimization of electrochemical sensors for H2O2 sensing. The different devices are compared on the basis of the sensitivity values, the limit of detection (LOD) and the linear range of application reported in the literature. The review aims to provide an overview of the advantages associated with different nanostructures to assess which one best suits a target application.

Ribavirin and cellular ribavirin-triphosphate concentrations in blood and bronchoalveolar lavage fluid in two lung transplant patients with respiratory syncytial virus.

Respiratory syncytial virus (RSV) is responsible for significant morbidity and mortality in the lung transplant population. Oral and aerosolized ribavirin may improve outcomes in lung transplant patients with RSV; however, data relating ribavirin concentrations in plasma and intracellular ribavirin triphosphate (iRTP) concentrations in blood and bronchoalveolar lavage (BAL) fluid cells with efficacy and safety are lacking. We describe ribavirin and iRTP concentrations within various compartments in two adult lung transplant recipients with RSV who were sampled throughout successful treatment courses with oral and inhaled ribavirin. In patient 1, iRTP BAL concentrations decreased by 45% over 3 days after changing inhaled ribavirin to oral (6.32 to 3.43 pmol/106 cells). In patient 2, iRTP BAL concentrations were 103 pmol/106 cells after 5 days of oral followed by 5 days of inhaled ribavirin. Further study is needed to describe ribavirin pharmacokinetics in the respiratory compartment to inform clinical use of ribavirin for respiratory viruses.

The fungal subtilase AsES elicits a PTI-like defence response in Arabidopsis thaliana plants independently of its enzymatic activity.

Acremonium strictum elicitor subtilisin (AsES) is a 34-kDa serine-protease secreted by the strawberry fungal pathogen A. strictum. On AsES perception, a set of defence reactions is induced, both locally and systemically, in a wide variety of plant species and against pathogens of alternative lifestyles. However, it is not clear whether AsES proteolytic activity is required for triggering a defence response or if the protein itself acts as an elicitor. To investigate the necessity of the protease activity to activate the defence response, AsES coding sequences of the wild-type gene and a mutant on the active site (S226A) were cloned and expressed in Escherichia coli. Our data show that pretreatment of Arabidopsis plants with inactive proteins, i.e. inhibited with phenylmethylsulphonyl fluoride (PMSF) and mutant, resulted in an increased systemic resistance to Botrytis cinerea and expression of defence-related genes in a temporal manner that mimics the effect already reported for the native AsES protein. The data presented in this study indicate that the defence-eliciting property exhibited by AsES is not associated with its proteolytic activity. Moreover, the enhanced expression of some immune marker genes, seedling growth inhibition and the involvement of the co-receptor BAK1 observed in plants treated with AsES suggests that AsES is being recognized as a pathogen-associated molecular pattern by a leucine-rich repeat receptor. The understanding of the mechanism of action of AsES will contribute to the development of new breeding strategies to confer durable resistance in plants.

Cross-talk between the RcsCDB and RstAB systems to control STM1485 gene expression in Salmonella Typhimurium during acid-resistance response.

Bacterial survive and respond to adverse changes in the environment by regulating gene transcription through two-component regulatory systems. In Salmonella Typhimurium the STM1485 gene expression is induced under low pH (4.5) during replication inside the epithelial host cell, but it is not involved in sensing or resisting to this condition. Since the RcsCDB system is activated under acidic conditions, we investigated whether this system is able to modulate STM1485 expression. We demonstrated that acid-induced activation of the RcsB represses STM1485 transcription by directly binding to the promoter. Under the same condition, the RstA regulator activates the expression of this gene. Physiologically, we observed that RcsB-dependent repression is required for the survival of bacteria when they are exposed to pancreatic fluids. We hypothesized that STM1485 plays an important role in Salmonella adaptation to pH changes, during transition in the gastrointestinal tract. We suggest that bacteria surviving the gastrointestinal environment invade the epithelial cells, where they can remain in vacuoles. In this new environment, acidity and magnesium starvation activate the expression of the RstA regulator in a PhoPQ-dependent manner, which in turn induces STM1485 expression. These levels of STM1485 allow increased bacterial replication within vacuoles to continue the course of infection.

Surgery for patients with Alpha 1 Antitrypsin Deficiency: A review.

BACKGROUND: Alpha 1 Antitrypsin Deficiency (AATD) is a genetic cause of emphysema/chronic obstructive pulmonary disease (COPD) and liver disease, making AATD patients a high-risk surgical group. Additionally, patients may eventually require lung and/or liver transplantation or lung volume reduction surgery (LVRS). This narrative review discusses perioperative considerations for elective procedures in AATD patients, and reviews patient outcomes in AATD-related transplantation and LVRS. DATA SOURCES: PubMed search terms included: "pre-/peri-/post-operative management"; "COPD"; "AATD"; "lung/liver transplant"; "lung volume reduction." CONCLUSIONS: Lung and liver transplantation in AATD patients are associated with very good long-term survival rates that are comparable to, and sometimes superior to, other transplant indications. Although not currently recommended in AATD, LVRS may have a role in a minority of patients. The value of Alpha 1 Antitrypsin (AAT) augmentation therapy following lung transplantation requires further study. Wherever possible, AAT therapy should be continued in the period around elective surgeries.

Report from the American Society of Transplantation on frailty in solid organ transplantation.

A consensus conference on frailty in kidney, liver, heart, and lung transplantation sponsored by the American Society of Transplantation (AST) and endorsed by the American Society of Nephrology (ASN), the American Society of Transplant Surgeons (ASTS), and the Canadian Society of Transplantation (CST) took place on February 11, 2018 in Phoenix, Arizona. Input from the transplant community through scheduled conference calls enabled wide discussion of current concepts in frailty, exploration of best practices for frailty risk assessment of transplant candidates and for management after transplant, and development of ideas for future research. A current understanding of frailty was compiled by each of the solid organ groups and is presented in this paper. Frailty is a common entity in patients with end-stage organ disease who are awaiting organ transplantation, and affects mortality on the waitlist and in the posttransplant period. The optimal methods by which frailty should be measured in each organ group are yet to be determined, but studies are underway. Interventions to reverse frailty vary among organ groups and appear promising. This conference achieved its intent to highlight the importance of frailty in organ transplantation and to plant the seeds for further discussion and research in this field.

Anti-LFA-1 induces CD8 T-cell dependent allograft tolerance and augments suppressor phenotype CD8 cells.

The induction of tolerance to transplanted organs is a major objective in transplantation immunology research. Lymphocyte function-associated antigen-1 (LFA-1) interactions have been identified as a key component of the T-cell activation process that may be interrupted to lead to allograft tolerance. In mice, αLFA-1 mAb is a potent monotherapy that leads to the induction of donor-specific transferable tolerance. By interrogating important adaptive and innate immunity pathways, we demonstrate that the induction of tolerance relies on CD8+T-cells. We further demonstrate that αLFA-1 induced tolerance is associated with CD8+CD28-T-cells with a suppressor phenotype, and that while CD8 cells are present, the effector T-cell response is abrogated. A recent publication has shown that CD8+CD28- cells are not diminished by cyclosporine or rapamycin, therefore CD8+CD28- cells represent a clinically relevant population. To our knowledge, this is the first time that a mechanism for αLFA-1 induced tolerance has been described.

Soft mechanical stimulation induces a defense response against Botrytis cinerea in strawberry.

KEY MESSAGE: Genes associated with plant mechanical stimulation were found in strawberry genome. A soft mechanical stimulation (SMS) induces molecular and biochemical changes in strawberry plants, conferring protection against Botrytis cinerea. Plants have the capacity to induce a defense response after exposure to abiotic stresses acquiring resistance towards pathogens. It was reported that when leaves of Arabidopsis thaliana were wounded or treated with a soft mechanical stimulation (SMS), they could resist much better the attack of the fungal pathogen Botrytis cinerea, and this effect was accompanied by an oxidative burst and the expression of touch-inducible genes (TCH). However, no further work was carried out to better characterize the induced defense response. In this paper, we report that TCH genes were identified for first time in the genomes of the strawberry species Fragaria ananassa (e.g. FaTCH2, FaTCH3, FaTCH4 and FaCML39) and Fragaria vesca (e.g. FvTCH2, FvTCH3, FvTCH4 and FvCML39). Phylogenetic studies revealed that F. ananassa TCH genes exhibited high similarity with the orthologous of F. vesca and lower with A. thaliana ones. We also present evidence that after SMS treatment on strawberry leaves, plants activate a rapid oxidative burst, callose deposition, and the up-regulation of TCH genes as well as plant defense genes such as FaPR1, FaCHI2-2, FaCAT, FaACS1 and FaOGBG-5. The latter represents the first report showing that TCH- and defense-induced genes participate in SMS-induced resistance in plants, bringing a rational explanation why plants exposed to a SMS treatment acquired an enhance resistance toward B. cinerea.

The Elicitor Protein AsES Induces a Systemic Acquired Resistance Response Accompanied by Systemic Microbursts and Micro-Hypersensitive Responses in Fragaria ananassa.

The elicitor AsES (Acremonium strictum elicitor subtilisin) is a 34-kDa subtilisin-like protein secreted by the opportunistic fungus Acremonium strictum. AsES activates innate immunity and confers resistance against anthracnose and gray mold diseases in strawberry plants (Fragaria × ananassa Duch.) and the last disease also in Arabidopsis. In the present work, we show that, upon AsES recognition, a cascade of defense responses is activated, including: calcium influx, biphasic oxidative burst (O2⋅- and H2O2), hypersensitive cell-death response (HR), accumulation of autofluorescent compounds, cell-wall reinforcement with callose and lignin deposition, salicylic acid accumulation, and expression of defense-related genes, such as FaPR1, FaPG1, FaMYB30, FaRBOH-D, FaRBOH-F, FaCHI23, and FaFLS. All these responses occurred following a spatial and temporal program, first induced in infiltrated leaflets (local acquired resistance), spreading out to untreated lateral leaflets, and later, to distal leaves (systemic acquired resistance). After AsES treatment, macro-HR and macro-oxidative bursts were localized in infiltrated leaflets, while micro-HRs and microbursts occurred later in untreated leaves, being confined to a single cell or a cluster of a few epidermal cells that differentiated from the surrounding ones. The differentiated cells initiated a time-dependent series of physiological and anatomical changes, evolving to idioblasts accumulating H2O2 and autofluorescent compounds that blast, delivering its content into surrounding cells. This kind of systemic cell-death process in plants is described for the first time in response to a single elicitor. All data presented in this study suggest that AsES has the potential to activate a wide spectrum of biochemical and molecular defense responses in F. ananassa that may explain the induced protection toward pathogens of opposite lifestyle, like hemibiotrophic and necrotrophic fungi.

Pharmacologic Protection of Mitochondrial DNA Integrity May Afford a New Strategy for Suppressing Lung Ischemia-Reperfusion Injury.

Lung ischemia-reperfusion (IR) injury contributes to post-transplant complications, including primary graft dysfunction. Decades of reports show that reactive oxygen species generated during lung IR contribute to pulmonary vascular endothelial barrier disruption and edema formation, but the specific target molecule(s) that "sense" injury-inducing oxidant stress to activate signaling pathways culminating in pathophysiologic changes have not been established. This review discusses evidence that mitochondrial DNA (mtDNA) may serve as a molecular sentinel wherein oxidative mtDNA damage functions as an upstream trigger for lung IR injury. First, the mitochondrial genome is considerably more sensitive than nuclear DNA to oxidant stress. Multiple studies suggest that oxidative mtDNA damage could be transduced to physiologic dysfunction by pathways that are either a direct consequence of mtDNA damage per se or involve formation of proinflammatory mtDNA damage-associated molecular patterns. Second, transgenic animals or cells overexpressing components of the base excision DNA repair pathway in mitochondria are resistant to oxidant stress-mediated pathophysiologic effects. Finally, published and preliminary studies show that pharmacologic enhancement of mtDNA repair or mtDNA damage-associated molecular pattern degradation suppresses reactive oxygen species-induced or IR injury in multiple organs, including preclinical models of lung procurement for transplant. Collectively, these findings point to the interesting prospect that pharmacologic enhancement of DNA repair during procurement or ex vivo lung perfusion may increase the availability of lungs for transplant and reduce the IR injury contributing to primary graft dysfunction.

Metástasis en troides de tumores primarios extratroideos / Thyroidal metastasis of primary extrathyroidal tumors

Antecedentes: las metástasis en tiroides son infrecuentes, pocas veces diagnosticadas antes de la cirugía; sin embargo, las autopsias muestran una frecuencia que oscila entre el 1 y el 24%. Objetivo: presentar nuestra estadística de metástasis en tiroides de tumores extratiroideos y citar una metástasis a los 23 años del tumor renal primario. Material y métodos: estudio retrospectivo estadístico sobre 1000 tiroidectomías y sus hallazgos histológicos, en un Hospital General. Resultados: en 1000 tiroidectomías, hallamos 3 metástasis extratiroideas, 2 de riñón (un paciente masculino de 70 años con primario 9 años antes y una mujer de 73 años con primario 23 años antes) y uno de útero (pacientede 74 años con primario de 5 años antes). La metástasis del carcinoma renal fue la más frecuente. Conclusión: la localización de metástasis en tiroides es poco habitual pero debe ser considerada especialmente en aquellos enfermos con antecedentes de carcinomas.

Background: Although metastasis in the thyroid gland are rare and infrequently diagnosed, they can be found in 1 to 24% of all autopsies. Objective: to present our series of thyroidal metastasis, of extra thyroid primary tumors and to report one case of metastasis 23 years after a primary renal tumor. Material and methods: retrospective study of 1000 thyroidectomies and the histological findings in a General Hospital. Results: in 1000 thyroidectomies, we found 3 metastases of extrathyroid cancer, 2 renal (male 70 years old with 9 year prior primary, female 73 years old with a primary 23 years before) and a female 74 years old with a primary of uterus operated 5 years earlier. The renal metastases in thyroid were the most common. Conclusion: the localization of metastases in thyroid are unusual, but should be considered in patients with history of malignancy carcinomas.

Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation.

Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications.

ALN-RSV01 for prevention of bronchiolitis obliterans syndrome after respiratory syncytial virus infection in lung transplant recipients.

BACKGROUND: Respiratory syncytial virus (RSV) infection in lung transplant (LTx) patients is associated with an increased incidence of bronchiolitis obliterans syndrome (BOS). ALN-RSV01 is a small interfering RNA targeting RSV replication that was shown in an earlier Phase 2a trial to be safe and to reduce the incidence of BOS when compared with placebo. METHODS: We performed a Phase 2b randomized, double-blind, placebo-controlled trial in RSV-infected LTx patients to examine the impact of ALN-RSV01 on the incidence of new or progressive BOS. Subjects were randomized (1:1) to receive aerosolized ALN-RSV01 or placebo daily for 5 days. RESULTS: Of 3,985 symptomatic patients screened, 218 were RSV-positive locally, of whom 87 were randomized to receive ALN-RSV01 or placebo (modified intention-to-treat [mITT] cohort). RSV infection was confirmed by central laboratory in 77 patients (ALN-RSV01, n = 44; placebo, n = 33), which comprised the primary analysis cohort (central mITT [mITTc]). ALN-RSV01 was found to be safe and well-tolerated. At Day 180, in ALN-RSV01-treated patients, compared with placebo, in the mITTc cohort there was a trend toward a decrease in new or progressive BOS (13.6% vs 30.3%, p = 0.058), which was significant in the per-protocol cohort (p = 0.025). Treatment effect was enhanced when ALN-RSV01 was started <5 days from symptom onset, and was observed even without ribavirin treatment. There was no significant impact on viral parameters or symptom scores. CONCLUSIONS: These results confirm findings of the earlier Phase 2a trial and provide further support that ALN-RSV01 reduces the risk of BOS after RSV in LTx recipients.

Continued Utility of Single-Lung Transplantation in Select Populations: Chronic Obstructive Pulmonary Disease.

BACKGROUND: The use of single lung transplantation (SLTx) for chronic obstructive pulmonary disease is often viewed as inferior therapy compared with bilateral lung transplantation (BLTx). We hypothesized from our experience that subpopulations of recipients with emphysema exist in which SLTx represents therapy that is equivalent to BLTx, therefore allowing more patients access to transplantation. METHODS: Consecutive patients undergoing LTx for emphysema between 1992 and 2012 at a single institution were identified and analyzed retrospectively. A similar cohort from the United Network of Organ Sharing (UNOS) national database was identified for comparison. Five-year survival in patients receiving SLTx and those receiving BLTx were compared using Kaplan-Meier survival curves and log-rank tests. RESULTS: Two hundred thirty-six patients meeting criteria were identified from our institution. Two hundred six underwent SLTx, and 30 underwent BLTx. Five-year survival for single-center SLTx (53.2% ± 3.6%) and BLTx (56.7% ± 10.2%) was not significantly different (p = 0.753). The national database included 7,256 patients meeting selection criteria, with 4,408 undergoing SLTx and 2,848 undergoing BLTx. Five-year survival among the national cohorts was lower for SLTx (46.4% ± 0.8%) compared with BLTx (55.9% ± 1.1%) (p < 0.0001). However, 5-year survival for our single-center SLTx experience (53.2% ± 3.6%) was comparable to the national BLTx cohort (55.9% ± 1.1%) (p = 0.539). CONCLUSIONS: Five-year survival after SLTx for emphysema was comparable to that for BLTx in cohorts from our institution and from the UNOS national database. Further study should focus on the mechanism behind these improved outcomes. Given the potential for a larger number of life-years saved, SLTx should continue to be considered a therapeutic option in appropriately selected patients with chronic obstructive pulmonary disease (COPD).

Invasive Microascus trigonosporus Species Complex Pulmonary Infection in a Lung Transplant Recipient.

Because of the high incidence of morbidity and mortality associated with invasive fungal infections, antifungal prophylaxis is often used in solid organ transplant recipients. However, this prophylaxis is not universally effective and may contribute to the selection of emerging, resistant pathogens. Here we present a rare case of invasive infection caused by Microascus trigonosporus species complex in a human, which developed during voriconazole prophylaxis in a lung transplant recipient. Nebulized liposomal amphotericin B was used in addition to systemic therapy in order to optimize antifungal drug exposure; this regimen appeared to reduce the patient's fungal burden. Despite this apparent improvement, the patient's pulmonary status progressively declined in the setting of multiple comorbidities, ultimately leading to respiratory failure and death.

A consensus document for the selection of lung transplant candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.

The appropriate selection of lung transplant recipients is an important determinant of outcomes. This consensus document is an update of the recipient selection guidelines published in 2006. The Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT) organized a Writing Committee of international experts to provide consensus opinion regarding the appropriate timing of referral and listing of candidates for lung transplantation. A comprehensive search of the medical literature was conducted with the assistance of a medical librarian. Writing Committee members were assigned specific topics to research and discuss. The Chairs of the Writing Committee were responsible for evaluating the completeness of the literature search, providing editorial support for the manuscript, and organizing group discussions regarding its content. The consensus document makes specific recommendations regarding the timing of referral and of listing for lung transplantation. These recommendations include discussions not present in previous ISHLT guidelines, including lung allocation scores, bridging to transplant with mechanical circulatory and ventilator support, and expanded indications for lung transplantation. In the absence of high-grade evidence to support decision making, these consensus guidelines remain part of a continuum of expert opinion based on available studies and personal experience. Some positions are immutable. Although transplant is rightly a treatment of last resort for end-stage lung disease, early referral allows proper evaluation and thorough patient education. Subsequent waiting list activation implies a tacit agreement that transplant offers a significant individual survival advantage. It is both the challenge and the responsibility of the transplant community globally to ensure organ allocation maximizes the potential benefits of a scarce resource, thereby achieving that advantage.