Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine.

Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common SNPs. The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis and clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. In addition, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multiomic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations.

Bronchiolitis obliterans syndrome after lung or haematopoietic stem cell transplantation: current management and future directions.

Bronchiolitis obliterans syndrome (BOS) may develop after either lung or haematopoietic stem cell transplantation (HSCT), with similarities in histopathological features and clinical manifestations. However, there are differences in the contributory factors and clinical trajectories between the two conditions. BOS after HSCT occurs due to systemic graft-versus-host disease (GVHD), whereas BOS after lung transplantation is limited to the lung allograft. BOS diagnosis after HSCT is more challenging, as the lung function decline may occur due to extrapulmonary GVHD, causing sclerosis or inflammation in the fascia or muscles of the respiratory girdle. Treatment is generally empirical with no established effective therapies. This review provides rare insights and commonalities of both conditions, which are not well elaborated elsewhere in contemporary literature, and highlights the importance of cross disciplinary learning from experts in other transplant modalities. Treatment algorithms for each condition are presented, based on the published literature and consensus clinical opinion. Immunosuppression should be optimised, and other conditions or contributory factors treated where possible. When initial treatment fails, the ultimate therapeutic option is lung transplantation (or re-transplantation in the case of BOS after lung transplantation) in carefully selected candidates. Novel therapies under investigation include aerosolised liposomal cyclosporine, Janus kinase inhibitors, antifibrotic therapies and (in patients with BOS after lung transplantation) B-cell-directed therapies. Effective novel treatments that have a tangible impact on survival and thereby avoid the need for lung transplantation or re-transplantation are urgently required.

Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation.

Tens of thousands of patients with advanced lung diseases may be eligible to be considered as potential candidates for lung transplant around the world each year. The timing of referral, evaluation, determination of candidacy, and listing of candidates continues to pose challenges and even ethical dilemmas. To address these challenges, the International Society for Heart and Lung Transplantation appointed an international group of members to review the literature, to consider recent advances in the management of advanced lung diseases, and to update prior consensus documents on the selection of lung transplant candidates. The purpose of this updated consensus document is to assist providers throughout the world who are caring for patients with pulmonary disease to identify potential candidates for lung transplant, to optimize the timing of the referral of these patients to lung transplant centers, and to provide transplant centers with a framework for evaluating and selecting candidates. In addition to addressing general considerations and providing disease specific recommendations for referral and listing, this updated consensus document includes an ethical framework, a recognition of the variability in acceptance of risk between transplant centers, and establishes a system to account for how a combination of risk factors may be taken into consideration in candidate selection for lung transplantation.

Incidence of early diaphragmatic dysfunction after lung transplantation: results of a prospective observational study.

BACKGROUND: Diaphragmatic dysfunction is common after cardiothoracic surgery, but few studies report its incidence and consequences after lung transplantation. We aimed to estimate the incidence of diaphragmatic dysfunction using ultrasound in lung transplant patients up to 3 months postoperatively and evaluated the impact on clinical outcomes. METHODS: This was a single-center prospective observational cohort study of 27 lung transplant recipients using diaphragmatic ultrasound preoperatively, at 1 day, 1 week, 1 month, and 3 months postoperatively. Diaphragmatic dysfunction was defined as excursion < 10 mm in men and < 9 mm in women during quiet breathing. Clinical outcomes measured included duration of mechanical ventilation, length of stay (LOS) in Intensive Care (ICU), and hospital LOS. RESULTS: Sixty-two percentage of recipients experienced new, postoperative diaphragmatic dysfunction, but the prevalence fell to 22% at 3 months. No differences in clinical outcomes were found between those with diaphragmatic dysfunction compared to those without. Patients who experienced diaphragmatic dysfunction at 1 day postoperatively were younger and had a lower BMI than those who did not. CONCLUSIONS: Diaphragmatic dysfunction is common after lung transplant, improves significantly within 3 months, and did not impact negatively on duration of mechanical ventilation, LOS in ICU or hospital, or discharge destination.

The Impact of Resistant Bacterial Pathogens including Pseudomonas aeruginosa and Burkholderia on Lung Transplant Outcomes.

Pseudomonas and Burkholderia are gram-negative organisms that achieve colonization within the lungs of patients with cystic fibrosis, and are associated with accelerated pulmonary function decline. Multidrug resistance is a hallmark of these organisms, which makes eradication efforts difficult. Furthermore, the literature has outlined increased morbidity and mortality for lung transplant (LTx) recipients infected with these bacterial genera. Indeed, many treatment centers have considered Burkholderia cepacia infection an absolute contraindication to LTx. Ongoing research has delineated different species within the B. cepacia complex (BCC), with significantly varied morbidity and survival profiles. This review considers the current evidence for LTx outcomes between the different subspecies encompassed within these genera as well as prophylactic and management options. The availability of meta-genomic tools will make differentiation between species within these groups easier in the future, and will allow more evidence-based decisions to be made regarding suitability of candidates colonized with these resistant bacteria for LTx. This review suggests that based on the current evidence, not all species of BCC should be considered contraindications to LTx, going forward.

Endothelial to mesenchymal transition (EndMT) and vascular remodeling in pulmonary hypertension and idiopathic pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible fibrotic disease associated with respiratory failure. The disease remains idiopathic, but repeated alveolar epithelium injury, disruption of alveolar-capillary integrity, abnormal vascular repair, and pulmonary vascular remodeling are considered possible pathogenic mechanisms. Also, the development of comorbidities such as pulmonary hypertension (PH) could further impact disease outcome, quality of life and survival rates in IPF. AREAS COVERED: The current review provides a comprehensive literature survey of the mechanisms involved in the development and manifestations of IPF and their links to PH pathology. This review also provides the current understanding of molecular mechanisms that link the two pathologies and will specifically decipher the role of endothelial to mesenchymal transition (EndMT) along with the possible triggers of EndMT. The possibility of targeting EndMT as a therapeutic option in IPF is discussed. EXPERT OPINION: With a steady increase in prevalence and mortality, IPF is no longer considered a rare disease. Thus, it is of utmost importance and urgency that the underlying profibrotic pathways and mechanisms are fully understood, to enable the development of novel therapeutic strategies.

Timing it right: the challenge of recipient selection for lung transplantation.

Selection criteria for the referral and potential listing of patients for lung transplantation (LTx) have changed considerably over the last three decades but one key maxim prevails, the ultimate focus is to increase longevity and quality of life by careful utilization of a rare and precious resource, the donor organs. In this article, we review how the changes have developed and the outcomes of those changes, highlighting the impact of the lung allocation score (LAS) system. Major diseases, including interstitial lung disease (ILD), chronic obstructive pulmonary disease and pulmonary hypertension are considered in detail as well as the concept of retransplantation where appropriate. Results from bridging to LTx using extracorporeal membrane oxygenation (ECMO) are discussed and other potential contraindications evaluated such as advanced age, frailty and resistant infections. Given the multiplicity of risk factors it is a credit to those working in the field that such excellent and improving results are obtained with an ongoing dedication to achieving best practice.

Lung transplantation: a review of the optimal strategies for referral and patient selection.

One of the great challenges of lung transplantation is to bridge the dichotomy between supply and demand of donor organs so that the maximum number of potential recipients achieve a meaningful benefit in improvements in survival and quality of life. To achieve this laudable goal is predicated on choosing candidates who are sufficiently unwell, in fact possessing a terminal respiratory illness, but otherwise fit and able to undergo major surgery and a prolonged recuperation and rehabilitation stage combined with ongoing adherence to complex medical therapies. The choice of potential candidate and the timing of that referral is at times perhaps more art than science, but there are a number of solid guidelines for specific illnesses to assist the interested clinician. In this regard, the relationship between the referring clinician and the lung transplant unit is a critical one. It is an ongoing and dynamic process of education and two way communication, which is a marker of the professionalism of a highly performing unit. Lung transplantation is ultimately a team effort where the recipient is the key player. That principle has been enshrined in the three consensus position statements regarding selection criteria for lung and heart-lung transplantation promulgated by the International Society for Heart and Lung Transplantation over the last two decades. During this period, the number of indications for lung transplantation have broadened and the number of contraindications reduced. Risk management is paramount in the pre- and perioperative period to effect early successful outcomes. While it is not the province of this review to reiterate the detailed listing of those factors, an overview position will be developed that describes the rationale and evidence for selected criteria where that exists. Importantly, the authors will attempt to provide an historical and experiential basis for making these important and life-determining decisions. The reviews of this paper are available via the supplementary material section.

Favorable Outcome of Lung Transplantation for Severe Pulmonary Graft Versus Host Disease: An Australian Multicenter Case Series.

BACKGROUND: Severe pulmonary chronic graft versus host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation. Few treatments influence outcome, with 5-year overall survival as low as 13%. Lung transplantation (LTx) has been reported in small numbers of patients worldwide. METHODS: We investigated the outcomes of LTx performed for this indication at 2 large Australian LTx centers. RESULTS: Eighteen patients (aged 10-64 y; median, 29.6 y) received bilateral deceased lung transplants for pulmonary chronic GVHD between 2002 and 2017. LTx was performed at a median of 8.6 years after allogeneic stem cell transplantation (range, 2-23 y) with a median interval of 16 months from the time of transplant unit review to LTx. There were 2 early infective deaths and 3 further deaths from pulmonary infection and lung allograft rejection. There were no primary disease relapses. At a median follow-up of 5 years, the 5-year overall survival post-LTx is 80% and comparable to the Australia and New Zealand registry data of 64% for LTx performed for all indications. CONCLUSIONS: From one of the largest series of deceased LTx for this indication, we conclude that it is a feasible option for selected patients with severe pulmonary GVHD. The outcomes appear superior to that of non-LTx-based therapies and similar to the survival of the general LTx population. Establishing guidance on referral triggers, patient eligibility, organ selection, prophylaxis of allograft rejection, and supportive care would assist hematopoietic and lung transplant units in optimizing resource allocation and patient outcomes.

Nonmelanoma Skin Cancer Frequency and Risk Factors in Australian Heart and Lung Transplant Recipients.

Importance: There is limited research examining the incidence of nonmelanoma skin cancer (NMSC) in heart and lung transplant recipients in Australia. Objective: To determine the frequency of and risk factors for NMSC in a cohort of Australian heart and lung transplant recipients. Design, Setting, and Participants: A retrospective cohort study was conducted at an Australian tertiary center where heart and lung transplants are performed between March 21 and December 14, 2016. A consecutive sample of 94 patients who underwent heart and/or lung transplant presenting for outpatient dermatologic review were evaluated. Data analysis was conducted between April 18 and October 30, 2017. Exposures: Risk factors examined for association with posttransplantation NMSC included age at the time of transplantation, sex, skin phenotype, UV radiation exposure, history of allograft rejection, history of smoking, history of skin cancer prior to transplant, and transplant type. Main Outcomes and Measures: The primary outcome measure was the occurrence of posttransplantation NMSC. The probabilities of developing NMSC in general, and squamous cell carcinoma and basal cell carcinoma specifically, were separately summarized based on Kaplan-Meier analysis. Association of risk factors with development of NMSC was examined using univariable and multivariable Cox proportional hazards regression analysis. Results: Of the 94 study participants, 58 (62%) were men; median age at transplantation was 51.9 years (range, 15.1-69.7 years). There were 801 posttransplantation skin cancers in 57 (61%) of the patients who underwent heart and/or lung transplant. The probabilities for NMSC were 41% (95% CI, 31%-53%) at 5 years and 67% (95% CI, 55%-78%) at 10 years; for basal cell carcinoma, 27% (95% CI, 18%-38%) at 5 years and 53% (95% CI, 40%-67%) at 10 years; and for squamous cell carcinoma, 33% (95% CI, 24%-45%) at 5 years and 62% (95% CI, 50%-74%) at 10 years. On multivariable analysis, older age at transplantation was associated with the development of NMSC (hazard ratio [HR], 1.07/1 year; 95% CI, 1.04-1.10; P < .001) and history of pretransplant skin cancer was associated with development of basal cell carcinoma (HR, 4.56; 95% CI, 1.67-12.42; P = .003). A Fitzpatrick skin type III to VI was associated with a decreased risk of NMSC (HR, 0.42; 95% CI, 0.24-0.74; P = .003). Sex, transplanted organ, UV radiation exposure, and history of allograft rejection were not associated with an increased risk of skin cancer. Conclusions and Relevance: In this study of Australian heart and lung transplant recipients, there was a probable high frequency of NMSC. Routine dermatologic surveillance at frequent intervals is advised for similar populations.

Lung transplantation for non-small cell lung cancer and multifocal bronchioalveolar cell carcinoma.

Lung transplantation for primary bronchogenic cancer could lead to increased survival and improved quality of life for patients who have malignant disease, for which other therapies might be inappropriate. This Review examines the development of experience and outcomes for this indication and explores the limitations that are inherent in lung transplantation for malignant disease. Bronchogenic malignancy is a rare indication for lung transplantation constituting only 0·13% of all lung transplants in the USA from 1987 to 2010 and is only indicated for early-stage disease when conventional surgical techniques are contraindicated by poor lung function in which an unacceptably high risk of short-term mortality is expected. Outcomes can be extrapolated from the experience of finding an unexpected malignancy in an explanted lung for which approximately 30% of recipients, dependent on stage, succumb from distant metastatic disease in the first few years after transplant, after which long-term survival is similar to transplantation for other conditions. Care must be taken for lung transplantation for multifocal bronchoalveolar cell carcinoma to ensure that the donor lung is not contaminated with residual bronchoalveolar cell carcinoma cells in the upper airways during surgical implantation. The rarity of lung transplantation for cancer, and the absence of head-to-head trials comparing lung transplantation with conventional cancer care, limit the conclusions that can be drawn about lung transplantation for this indication. Furthermore, the ethical balance of how to allocate a scarce resource, such as a donor lung, remains an unresolved dilemma given the uncertainties regarding long-term survival. Conversely, individual patients might have substantial increases in survival and quality of life equivalent or superior to conventional cancer treatment methods.

High prevalence of diabetes before and after lung transplantation: target for improving outcome?

BACKGROUND: Diabetes increases morbidity and mortality of lung transplantation. However, the reported prevalence of diabetes varies post-transplantation partly due to lack of detection protocols. AIM: To determine the prevalence of diabetes in patients (i) waitlisted for lung transplant and (ii) early post-transplantation. METHODS: We analysed patients on the St Vincent's Heart Lung database from 1 April 2014 to 30 September 2015 on the waitlist (Study 1) and those transplanted (Study 2). Standard of care required all non-diabetic patients to have an oral glucose tolerance test (modified for patients with cystic fibrosis (CF) to screen for CF-related hyperglycaemia (CFRH) (plasma glucose ≥8.2 mmol/L at 60 or 90 min). RESULTS: Study 1 included 114 patients (32 with CF and 82 without CF). Of 30 CF patients with glycaemic data, 27 (90%) had abnormal glucose metabolism: 18 had diabetes and nine had CFRH. In 50 patients without CF, 20 (40%) had abnormal glucose metabolism: eight had diabetes and 12 had impaired fasting glucose and/or impaired glucose tolerance. Study 2 included 78 transplanted patients (25 with CF and 53 without CF). Fourteen CF patients had pre-existing diabetes and seven had pre-existing CFRH. All but one patient were diagnosed with diabetes post-transplantation. Hence, diabetes prevalence in CF patients post-transplantation was 96%. Among 53 transplanted patients without CF, seven (13%) had abnormal glucose metabolism but 30 (57%) were diagnosed with post-transplant diabetes. CONCLUSION: There is a high prevalence of diabetes in lung transplant patients. Earlier endocrine participation in lung transplant services is likely to lower diabetes-related morbidity and mortality further.

Systematic review and meta-analysis of post-transplant lymphoproliferative disorder in lung transplant recipients.

A systematic review of papers in English on post-transplant lymphoproliferative disorder (PTLD) in lung transplant recipients (LTR) using MEDLINE, EMBASE, SCOPUS, and Cochrane databases was performed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were strictly adhered to. Pooled odds ratios (pOR) were calculated from a random-effects model, and heterogeneity among studies was quantitated using I2 values. Fourteen studies published from 2005 to 2015 were included in the meta-analysis. One hundred and sixty-four lung transplant recipients were included. LTRs who received single vs bilateral were associated with a 7.67-fold risk of death after PTLD (6 studies with 64 LTRs; pOR 7.67 95% CI 1.98-29.70; P = .003). pOR of death for early onset PTLD (<1 year post-LT) vs late onset (>1 year post-LT) was not different (3 studies with 72 LTRS; pOR 0.62, 95% CI 0.20-1.86, P = .39). Standardized mean difference (SMD) in time from transplant to PTLD onset between LTRs who died vs alive was not different (9 studies with 109 LTRs; SMD 0.03, 95% CI -0.48-0.53, P = .92). Survival in polymorphic vs monomorphic PTLD and extranodal vs nodal disease was similar (4 studies with 31 LTRs; pOR 0.44, 95% CI 0.08-2.51; P = .36. 6 studies with 81 LTRs; pOR 1.05 95% CI 0.31-3.52, P = .94). This meta-analysis demonstrates that single LTRs are at a higher risk of death vs bilateral LTRs after the development of PTLD.

Herpes simplex virus-2 transmission following solid organ transplantation: Donor-derived infection and transplantation from prior organ recipients.

BACKGROUND: Owing to limited availability of donor organs, previous solid organ transplant (SOT) recipients are increasingly considered as potential organ donors. We report donor-derived transmission of herpes simplex virus type-2 (HSV-2) to two clusters of SOT recipients with transmission from the original donor and an HSV-2-infected recipient who subsequently became a donor. METHODS: We reviewed medical records of the donors and recipients in both clusters. Pre-transplant serology and virological features of HSV-2 were characterized. Genotyping of HSV-2 isolates to determine potential for donor transmission of HSV-2 through transplantation of organs from prior organ recipients was performed. RESULTS: A kidney-pancreas recipient died day 9 post transplant. Following confirmation of brain death, the lungs and recently transplanted kidney were donated to two further recipients. The liver was not retrieved, but biopsy confirmed HSV-2 infection. Testing on the original donor showed negative HSV-2 polymerase chain reaction and HSV immunoglobulin (Ig)M, but positive HSV-2 IgG. The liver recipient from the original donor developed HSV-2 hepatitis and cutaneous infection that responded to treatment with intravenous acyclovir. In the second cluster, lung and kidney recipients both developed HSV-2 viremia that was successfully treated with antiviral therapy. Genotyping of all HSV-2-positive samples showed 100% sequence homology for three recipients. CONCLUSIONS: Donor-derived HSV infection affected two clusters of recipients because of transplantation of organs from a prior organ recipient. HSV should be considered as a possible cause of illness in febrile SOT recipients in the immediate post-transplant period and may cause disseminated disease and re-infection in HSV-2-seropositive recipients. Testing of HSV serology and prophylaxis may be considered in SOT recipients not receiving cytomegalovirus prophylaxis.

Chest pain and recurrent chylothorax: an unusual presentation of malignant pleural mesothelioma.

Malignant mesothelioma presenting with recurrent chylous effusion is rare. We describe the case of a 34-year-old female Macedonian immigrant who presented with central chest pain and subsequently a left-sided chylous pleural effusion. The diagnosis was made on pleural biopsy via video-assisted thoracoscopic surgery (VATS). Our case demonstrates the utility of thoracic magnetic resonance imaging (MRI) and the difficulties associated with pleural cytology and cervical lymph node biopsy in the establishment of a diagnosis of mesothelioma. It is a reminder that mesothelioma can metastasize to mediastinal and cervical lymph nodes, can occur in young people, and may present as a chylothorax.

Acute rejection.

Despite induction immunosuppression and the use of aggressive maintenance immunosuppressive regimens, acute allograft rejection following lung transplantation is still a problem with important diagnostic and therapeutic challenges. As well as causing early graft loss and mortality, acute rejection also initiates the chronic alloimmune responses and airway-centred inflammation that predispose to bronchiolitis obliterans syndrome (BOS), also known as chronic lung allograft dysfunction (CLAD), which is a major source of morbidity and mortality after lung transplantation. Cellular responses to human leukocyte antigens (HLAs) on the allograft have traditionally been considered the main mechanism of acute rejection, but the influence of humoral immunity is increasingly recognised. As with other several other solid organ transplants, antibody-mediated rejection (AMR) is now a well-accepted and distinct clinical entity in lung transplantation. While acute cellular rejection (ACR) has defined histopathological criteria, transbronchial biopsy is less useful in AMR and its diagnosis is complicated by challenges in the measurement of antibodies directed against donor HLA, and a determination of their significance. Increasing awareness of the importance of non-HLA antigens further clouds this issue. Here, we review the pathophysiology, diagnosis, clinical presentation and treatment of ACR and AMR in lung transplantation, and discuss future potential biomarkers of both processes that may forward our understanding of these conditions.

Age-related survival disparity associated with lung transplantation in cystic fibrosis: An analysis of the registry of the International Society for Heart and Lung Transplantation.

BACKGROUND: A survival advantage has been demonstrated for lung transplantation (LTx) in the cystic fibrosis (CF) population, but children may be at higher risk of post-transplant mortality than adults. METHODS: The registry of the International Society for Heart and Lung Transplantation (ISHLT) was queried for lung transplants performed during the period 1998 to 2014 in patients with CF. Period differences were assessed by dividing the sample into LTxs performed between 2006 and 2014 and those performed between 1998 and 2005. Age ≥18 years distinguished adult from pediatric recipients. Supplemental analyses of United States of America (USA) LTx recipients with CF utilized 1998 to 2014 data from the United Network for Organ Sharing (UNOS) registry. RESULTS: A total of 7,245 patients from the ISHLT registry were selected for analysis. Kaplan-Meier curves confirmed a survival disadvantage of children as compared to adults with CF in 2006 to 2014 (p<0.001), and in the earlier era of 1998 to 2005 (p = 0.002). Univariate Cox proportional hazards regression revealed that age <18 years at transplantation [hazard ratio (HR) = 1.367; 95% confidence interval (CI) 1.225 to 1.526; p < 0.001] and LTxs performed in 1998 to 2005 (HR = 1.131; 95% CI 1.042 to 1.227; p = 0.003) were associated with greater mortality hazard. Multivariable Cox regression adjusting for potential confounders and interacting LTx era with recipient age group confirmed the persistence of age-related survival disparities after LTx in CF in the contemporary era. Analysis of UNOS data demonstrated survival disparities between children and adult CF patients receiving LTx in majority-adult programs. CONCLUSIONS: An age-related survival disparity after LTx has persisted in the international CF population. Data from the USA suggest this disparity is not fully explained by differences in center volume between adult and pediatric programs in the contemporary era.

Patient-reported symptoms and functioning as indicators of mortality in advanced cystic fibrosis: A new tool for referral and selection for lung transplantation.

BACKGROUND: Despite well-known risk factors and predictive survival models, many patients with cystic fibrosis (CF) die while on the waiting list for lung transplant. We evaluated whether specific Cystic Fibrosis Questionnaire (CFQ-R) scales provide additional benefit to conventional tools in identifying referral timing and waitlist mortality. METHODS: From January 2010 to January 2015, 152 patients (34% on the waitlist) were evaluated with the CFQ-R and standard protocol quarterly. Data were used to explore the prognostic association of health-related quality of life. RESULTS: The Physical Functioning domain (PFD) of the CFQ-R predicted mortality in advanced CF disease better than habitual parameters (p = 0.005). For patients with the same forced expiratory volume in 1 sec (FEV1), a low score categorized patients with an increased risk of death. For patients with CF and FEV1 <30% predicted and a low Physical score, mortality rate was ~35% at 2 years. The best model for probability of inclusion on the waitlist was FEV1 % (p < 0.001, hazard ratio [HR] = 0.94; 95% confidence interval [CI] [0.90, 0.97]) and Physical Functioning (p = 0.013, HR = 0.96; 95% CI [0.95, 0.99]). The best model for probability of death similarly included FEV1 % (p = 0.09, HR = 0.97; 95% CI [0.94, 1.00]) and CFQ-R Physical Functioning score (p = 0.005, HR = 0.97; 95% CI [0.95, 0.99]). The Health Perception score showed similar results. A low Health Perception score combined with a high resting heart rate showed a trend for mortality. CONCLUSIONS: The CFQ-R may be an additional tool for guiding decisions to place a patient with CF on the waiting list for lung transplantation. The CFQ-R Physical Functioning and Health Perception scales were more accurate than conventional tools in predicting death before transplant.