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Background: Outcomes for individuals with cystic fibrosis (CF) have improved due to highly effective modulator therapy (HEMT). However, lung transplant (LTx) remains an important treatment for people with advanced lung disease. This study assessed attitudes and knowledge about LTx in the HEMT era., Methods: All patients from the University of Washington CF clinic were surveyed March 25-May 30, 2020. Questions addressed self-rated LTx preparedness and knowledge, as well as barriers and facilitators to discussing LTx. Demographic and clinical data were extracted from the electronic health record., Results: There were 159/224 (71%) responses. Respondents had a median forced expiratory volume in one second (FEV 1 ) of 70%, and 142 (89%) were on modulatory therapy. One hundred thirteen (71%) respondents felt that it was moderately or very important to be prepared to make decisions about LTx, though only 56 (35%) felt moderately or very prepared. Only 83 (30%) and 47 (52%) participants correctly answered questions about life expectancy and improved quality of life after LTx, respectively. Respondents with Medicaid insurance less frequently answered questions correctly. The most common barriers to discussing LTx were fear of being a burden on loved ones for 58 respondents (36%) and cost of LTx for 46 (29%). Most participants (94%) trusted their CF doctor, and 75% of participants selected trust as a facilitator for LTx discussions., Conclusions: Many individuals with CF, especially those with lower socioeconomic status, lacked knowledge and did not feel very prepared for decisions about LTx. Earlier education and discussions about LTx represent an area for improvement in CF care., (© 2024. The Author(s).)

People with CF (PwCF), particularly those with advanced lung disease (ALD), experience frequent respiratory symptoms. A major CF breakthrough was the approval of elexacaftor/tezacaftor/ivacaftor (ETI) in 2019, which has been shown to improve symptoms and lung function in the CF population, and decrease pulmonary exacerbations. The purpose of this study was to analyze longitudinal changes in respiratory symptoms over 24 months in ETI-treated and untreated PwCF with ALD Symptoms were measured among CF adults with ppFEV 1 < 40% (N = 48, 24 ETI-treated, 24 untreated) using the CFRSD-CRISS and the CFQ-R [respiratory]. Two multilevel growth models assessed the rate of change in symptoms overall and within the ETI-treated and untreated groups. PwCF on ETI had significantly lower symptom severity over 24 months than those not on ETI as measured by the CRISS and CFQ-R. The ETI-treated group maintained an -11.7 and +19.3 point difference(p<0.01) in CRISS and CFQ-R scores over the study compared to the non-ETI group, achieving minimal clinically important differences on average between groups on both instruments. No change in the symptom burden trajectory between groups was observed (p = 0.58). Even with ALD, ETI-treated PwCF have a lower respiratory burden than those not on ETI. This may be confounded by survivorship bias in the non-ETI group. Of note, in this ALD cohort, neither instrument demonstrated ceiling effects. Our results suggest that, while ETI has significantly improved the lived experience, PwCF with ALD are still plagued by respiratory symptoms., Competing Interests: Declaration of Competing Interest Authors Eliana R. Gill, Lauren E. Bartlett, Tijana Milinic, Nora Burdis, Joseph M. Pilewski, Jordan M. Dunitz, Siddhartha G. Kapnadak, Christopher H. Goss, and Kathleen J. Ramos report no conflicts of interest., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Lung transplantation is a common therapeutic option for individuals with cystic fibrosis (CF) and advanced lung disease, yet many individuals with CF are not appropriately referred for evaluation. The present study sought to enhance CF transplant referral guidelines by integrating patient-centered input to identify possible psychosocial barriers contributing to suboptimal referral for appropriate CF transplant candidates., Methods: As a component of developing the Cystic Fibrosis Foundation (CFF) Lung Transplant Referral Consensus Guidelines, we convened a focus group of lung transplant recipients with CF and two spouses of CF recipients. Each session involved standardized approaches to elicit qualitative, thematic content., Results: CF patients and caregivers characterized five areas for improvement, which were integrated into formal CFF referral guidelines. These included (a) timing of transplant discussion with CF providers, (b) accuracy of transplant-related knowledge and expectations, (c) stigma associated with the need for transplantation, (d) treatment team transition issues, and (e) social support and mental health concerns. Earlier introduction of transplant, greater details regarding manageable aspects of treatment, and greater provision of social support were all associated with better psychosocial experiences., Conclusions: Integrating patient-centered input into guideline development yielded important and previously unknown psychosocial barriers contributing to suboptimal transplant referral., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Healthcare coproduction engages patients and clinicians to design and execute services, yet little is known about tools that facilitate coproduction. Our objective was to understand uptake, experiences, benefits, and limitations of a dashboard to support patient-clinician partnerships within the cystic fibrosis (CF) community., Methods: People living with CF (PwCF) and clinicians co-designed a dashboard that displayed patient-reported and clinical data. Eight CF programmes, including 21 clinicians, and 131 PwCF participated in a pilot study of the dashboard. We conducted descriptive statistics and thematic analyses of surveys (82 PwCF; 21 clinicians); semi-structured interviews (13 PwCF; 8 care teams); and passively-collected usage data., Results: Two-thirds of the 82 PwCF used the dashboard during a visit, and 59% used it outside a visit. Among 48 PwCF using the dashboard outside the clinic, 92% viewed their health information and 46% documented concerns or requests. Most of the 21 clinicians used the dashboard to support visit planning (76%); fewer used it during a visit (48%). The dashboard supported discussions of what matters most (69% PwCF; 68% clinicians). Several themes emerged: access to patient outcomes data allows users to learn more deeply; participation in pre-visit planning matters; coproduction is made possible by inviting new ways to partner; and lack of integration with existing information technology (IT) systems is limiting., Conclusions: A dashboard was feasible to implement and use. Future iterations should provide patients access to their data, be simple to use, and integrate with IT systems in use by clinicians and PwCF., Competing Interests: Declaration of Competing Interest Jordan Dunitz, Adrienne Savant, Brooke Moore, Michelle Prickett, Terri Laguna, Cindy Brady, Morgan Soper, Sarah Jain, and Whitney Gore report grant subcontracts from Dartmouth College to conduct work associated with design and pilot-testing of CFHC. Eugene Nelson, Kathryn Sabadosa, and Aricca Van Citters report grant funding from the Robert Wood Johnson Foundation and Cystic Fibrosis Foundation. Alex Gifford reports grant funding from the Cystic Fibrosis Foundation. Terri Laguna reports grant funding from the Cystic Fibrosis Foundation and the National Institutes of Health, is a grant reviewer for the Cystic Fibrosis Foundation and a member of a National Institute of Health study section; and receives an honorarium for participating on a Physician Advisory Board for Vertex Pharmaceuticals. Eugene Nelson owns stock in Quality Data Management (QDM). Bruce Marshall, Jonathan Flath, Madeline Elmhirst, and Maureen Riordan report no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Culture-independent studies of cystic fibrosis lung microbiota have provided few mechanistic insights into the polymicrobial basis of disease. Deciphering the specific contributions of individual taxa to CF pathogenesis requires comprehensive understanding of their ecophysiology at the site of infection. We hypothesize that only a subset of CF microbiota are translationally active and that these activities vary between subjects. Here, we apply bioorthogonal non-canonical amino acid tagging (BONCAT) to visualize and quantify bacterial translational activity in expectorated sputum. We report that the percentage of BONCAT-labeled (i.e. active) bacterial cells varies substantially between subjects (6-56%). We use fluorescence-activated cell sorting (FACS) and genomic sequencing to assign taxonomy to BONCAT-labeled cells. While many abundant taxa are indeed active, most bacterial species detected by conventional molecular profiling show a mixed population of both BONCAT-labeled and unlabeled cells, suggesting heterogeneous growth rates in sputum. Differentiating translationally active subpopulations adds to our evolving understanding of CF lung disease and may help guide antibiotic therapies targeting bacteria most likely to be susceptible.

A critical limitation in the management of chronic polymicrobial infections is the lack of correlation between antibiotic susceptibility testing (AST) and patient responses to therapy. Underlying this disconnect is our inability to accurately recapitulate the in vivo environment and complex polymicrobial communities in vitro However, emerging evidence suggests that, if modeled and tested accurately, interspecies relationships can be exploited by conventional antibiotics predicted to be ineffective by standard AST. As an example, under conditions where Pseudomonas aeruginosa relies on cocolonizing organisms for nutrients (i.e., cross-feeding), multidrug-resistant P. aeruginosa may be indirectly targeted by inhibiting the growth of its metabolic partners. While this has been shown in vitro using synthetic bacterial communities, the efficacy of a "weakest-link" approach to controlling host-associated polymicrobial infections has not yet been demonstrated. To test whether cross-feeding inhibition can be leveraged in clinically relevant contexts, we collected sputa from cystic fibrosis (CF) subjects and used enrichment culturing to isolate both P. aeruginosa and anaerobic bacteria from each sample. Predictably, both subpopulations showed various antibiotic susceptibilities when grown independently. However, when P. aeruginosa was cultured and treated under cooperative conditions in which it was dependent on anaerobic bacteria for nutrients, the growth of both the pathogen and the anaerobe was constrained despite their intrinsic antibiotic resistance profiles. These data demonstrate that the control of complex polymicrobial infections may be achieved by exploiting obligate or facultative interspecies relationships. Toward this end, in vitro susceptibility testing should evolve to more accurately reflect in vivo growth environments and microbial interactions found within them. IMPORTANCE Antibiotic efficacy achieved in vitro correlates poorly with clinical outcomes after treatment of chronic polymicrobial diseases; if a pathogen demonstrates susceptibility to a given antibiotic in the lab, that compound is often ineffective when administered clinically. Conversely, if a pathogen is resistant in vitro , patient treatment with that same compound can elicit a positive response. This discordance suggests that the in vivo growth environment impacts pathogen antibiotic susceptibility. Indeed, here we demonstrate that interspecies relationships among microbiotas in the sputa of cystic fibrosis patients can be targeted to indirectly inhibit the growth of Pseudomonas aeruginosa The therapeutic implication is that control of chronic lung infections may be achieved by exploiting obligate or facultative relationships among airway bacterial community members. This strategy is particularly relevant for pathogens harboring intrinsic multidrug resistance and is broadly applicable to chronic polymicrobial airway, wound, and intra-abdominal infections., (Copyright © 2020 Flynn et al.)

Background: The increasing life expectancy of individuals with Cystic Fibrosis (CF) is likely to be associated with new age-related challenges, colorectal cancer (CRC) most notably; recent consensus recommendations for CRC screening published in 2018 represent an important early step in addressing the emerging awareness of CF as a gastrointestinal cancer syndrome. These recommendations, however, need to be further refined based on more systematic data. We discuss an illustrative first-ever case of synchronous CRC arising in a post-lung transplant individual with CF within the recommended surveillance interval after a well-documented prior normal colonoscopy., Case Presentation: A 51-year-old female individual with homozygous F508del CF, presents to clinic with abdominal discomfort and intermittent blood in stools. She had previously undergone bilateral lung transplantation 18 years earlier, as well as two kidney transplants related to immunosuppression-related nephrotoxicity. A diagnostic colonoscopy was performed which revealed the presence of two separate synchronous colon cancers in the cecum and transverse colon; she had undergone a colonoscopy three years prior to this exam which was structurally normal. Endoscopic quality indicators, including a good quality bowel preparation, colonoscopic withdrawal time > 12 min, and quarterly Adenoma Detection Rate (ADR) ranging from 50 to 70% for both male and female patients for the endoscopist from both colonoscopic exams, as well as secondary retrospective comparative review of the pertinent case images, diminish the risk for a "missed" cancer or advanced lesion on the index exam. These cancers did not demonstrate any immunohistochemical features suggestive of Lynch Syndrome, though the rapid progression to cancer within the surveillance interval (possibly non-polypoid in nature) is similar. This cancer presentation within the newly-established recommended colon cancer screening interval warrants concern., Conclusions: This case prompts serious discussion regarding the length of surveillance intervals in the post-transplant CF population (a population at 20-30 times greater risk for CRC compared to the general non-CF population), as well as the importance of documenting endoscopic quality benchmarks, particularly if a narrative of interval CRC development continues to develop with further prospective monitoring and multi-center experience.

Objective: Provide recommendations to the cystic fibrosis (CF) community to facilitate timely referral for lung transplantation for individuals with CF., Methods: The CF Foundation organized a multidisciplinary committee to develop CF Lung Transplant Referral Consensus Guidelines. Three workgroups were formed: timing for transplant referral; modifiable barriers to transplant; and transition to transplant care. A focus group of lung transplant recipients with CF and spouses of CF recipients informed guideline development., Results: The committee formulated 21 recommendation statements based on literature review, committee member practices, focus group insights, and in response to public comment. Critical approaches to optimizing access to lung transplant include early discussion of this treatment option, assessment for modifiable barriers to transplant, and open communication between the CF and lung transplant centers., Conclusions: These guidelines will help CF providers counsel their patients and may reduce the number of individuals with CF who die without consideration for lung transplant., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Rationale: Cystic fibrosis (CF) is characterized by dietary antioxidant deficiencies, which may contribute to an oxidant-antioxidant imbalance and oxidative stress., Objectives: Evaluate the effects of an oral antioxidant-enriched multivitamin supplement on antioxidant concentrations, markers of inflammation and oxidative stress, and clinical outcomes., Methods: In this investigator-initiated, multicenter, randomized, double-blind, controlled trial, 73 pancreatic-insufficient subjects with CF 10 years of age and older with an FEV 1 between 40% and 100% predicted were randomized to 16 weeks of an antioxidant-enriched multivitamin or control multivitamin without antioxidant enrichment. Endpoints included systemic antioxidant concentrations, markers of inflammation and oxidative stress, clinical outcomes (pulmonary exacerbations, anthropometric measures, pulmonary function), safety, and tolerability., Measurements and Main Results: Change in sputum myeloperoxidase concentration over 16 weeks, the primary efficacy endpoint, was not significantly different between the treated and control groups. Systemic antioxidant (β-carotene, coenzyme Q10, γ-tocopherol, and lutein) concentrations significantly increased in the antioxidant-treated group (P < 0.001 for each), whereas circulating calprotectin and myeloperoxidase decreased in the treated group compared with the control group at Week 4. The treated group had a lower risk of first pulmonary exacerbation requiring antibiotics than the control group (adjusted hazard ratio, 0.50; P = 0.04). Lung function and growth endpoints did not differ between groups. Adverse events and tolerability were similar between groups., Conclusions: Antioxidant supplementation was safe and well tolerated, resulting in increased systemic antioxidant concentrations and modest reductions in systemic inflammation after 4 weeks. Antioxidant treatment was also associated with a lower risk of first pulmonary exacerbation. Clinical trial registered with www.clinicaltrials.gov (NCT01859390).

Background: Metastasis of upper airway microbiota may have significant implications in the development of chronic lung disease. Here, we compare bacterial communities of matched sinus and lung mucus samples from cystic fibrosis (CF) subjects undergoing endoscopic surgery for treatment of chronic sinusitis., Methods: Mucus from one maxillary sinus and expectorated sputum were collected from twelve patients. 16S rRNA gene sequencing was then performed on sample pairs to compare the structure and function of CF airway microbiota., Results: Bacterial diversity was comparable between airway sites, though sinuses harbored a higher prevalence of dominant microorganisms. Ordination analyses revealed that samples clustered more consistently by airway niche rather than by individual. Finally, predicted metagenomes suggested that anaerobiosis was enriched in the lung., Conclusions: Our findings indicate that while the lung may be seeded by individual sinus pathogens, airway microenvironments harbor distinct bacterial communities that should be considered in selecting antimicrobial therapies., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Objectives: Chronic pancreatitis (CP) is an infrequent but debilitating complication associated with CFTR mutations. Total pancreatectomy with islet autotransplantation (TPIAT) is a treatment option for CP that provides pain relief and preserves β-cell mass, thereby minimizing the complication of diabetes mellitus. We compared outcomes after TPIAT for CP associated with CFTR mutations to CP without CTFR mutations., Methods: All TPIATs performed between 2002 and 2014 were retrospectively reviewed: identifying 20 CFTR homozygotes (cystic fibrosis [CF] patients), 19 CFTR heterozygotes, and 20 age-/sex-matched controls without CFTR mutations. Analysis of variance and χ tests were used to compare groups., Results: Baseline demographics were not different between groups. Postoperative glycosylated hemoglobin and C-peptide levels were similar between groups, as were islet yield and rate of postoperative complications. At 1 year, 40% of CF patients, 22% of CFTR heterozygotes, and 35% of control patients were insulin independent., Conclusion: Total pancreatectomy with islet autotransplantation is a safe, effective treatment option for CF patients with CP, giving similar outcomes for those with other CP etiologies.

Chronic lung infections in cystic fibrosis (CF) patients are composed of complex microbial communities that incite persistent inflammation and airway damage. Despite the high density of bacteria that colonize the lower airways, nutrient sources that sustain bacterial growth in vivo, and how those nutrients are derived, are not well characterized. In this study, we examined the possibility that mucins serve as an important carbon reservoir for the CF lung microbiota. While Pseudomonas aeruginosa was unable to efficiently utilize mucins in isolation, we found that anaerobic, mucin-fermenting bacteria could stimulate the robust growth of CF pathogens when provided intact mucins as a sole carbon source. 16S rRNA sequencing and enrichment culturing of sputum also identified that mucin-degrading anaerobes are ubiquitous in the airways of CF patients. The collective fermentative metabolism of these mucin-degrading communities in vitro generated amino acids and short chain fatty acids (propionate and acetate) during growth on mucin, and the same metabolites were also found in abundance within expectorated sputum. The significance of these findings was supported by in vivo P. aeruginosa gene expression, which revealed a heightened expression of genes required for the catabolism of propionate. Given that propionate is exclusively derived from bacterial fermentation, these data provide evidence for an important role of mucin fermenting bacteria in the carbon flux of the lower airways. More specifically, microorganisms typically defined as commensals may contribute to airway disease by degrading mucins, in turn providing nutrients for pathogens otherwise unable to efficiently obtain carbon in the lung., Competing Interests: The authors have declared that no competing interests exist.

Background: Colorectal cancer is an emerging problem in cystic fibrosis (CF). The goal of this study was to evaluate adenoma detection by systematic colonoscopic screening and surveillance., Methods: We analyzed prospectively collected results of colonoscopies initiated at age 40years from 88 CF patients at a single Cystic Fibrosis Center. We also reviewed results of diagnostic colonoscopies from 27 patients aged 30-39years performed during the same time period at the Center., Results: The incidence of polyp detection increased markedly after age 40 in CF patients. Greater than 50% were found to have adenomatous polyps; approximately 25% had advanced adenomas as defined by size and/or histopathology; 3% were found to have colon cancer. Multivariate analysis demonstrated specific risk factors for adenoma formation and progression., Conclusions: Early screening and more frequent surveillance should be considered in patients with CF due to early incidence and progression of adenomas in this patient population., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background and Goals: Cystic fibrosis (CF) is associated with increased incidence of gastrointestinal cancer. Increasing overall life expectancy of CF patients predicts emergence of colon cancer as a significant clinical problem in the adult CF population. The primary aim of this study was to estimate the incidence of adenomatous colon polyps in patients with CF during systematic screening by colonoscopy., Study: This is a single-center series of 45 CF patients aged 40 years and above (mean age, 47 y) undergoing colonoscopic screening. A fraction of these patients (9/45) had history of organ transplantation. Results from transplant and nontransplant patients were analyzed separately., Results: Adult CF patients have a high incidence of adenomatous polyps identified by colonoscopy. In addition, positive examinations are characterized by multiple polyps and common features of advanced pathology. The incidence of adenomatous colon polyps is greater in male patients, although the 1 patient in this cohort found to have colorectal cancer was female., Conclusions: CF has features of a hereditary colon cancer syndrome. Increasing life expectancy of CF patients suggests that earlier colon screening in this population may be warranted. Optimal criteria for initiation of screening and frequency of surveillance should be subject of further studies.

Background: Clostridium difficile infection (CDI) and associated mortality in solid organ transplant recipients is rising, but data are scarce in lung transplant recipients. We aimed to characterize CDI and its effect on mortality in a large cohort of lung transplant recipients., Methods: Lung transplant recipients were identified from our transplant database from 2000 to 2011. Cox proportional hazard models were used to calculate hazard ratios for CDI and death after adjusting for potential confounders identified from bivariate analysis., Results: We identified 388 patients (196 female, 192 male), with a median age of 56 years (range, 8-75 years), during the study period. CDI developed after transplant in 89 (22.9%), with 27 (7.0%) developing CDI during the initial hospitalization at a mean diagnosis of 12.7 ± 11.4 days. Incidence varied widely each year (median, 24%; range, 5%-32%), with the highest rates in 2007 to 2008. Post-operative length of stay was identified as a significant predictor of CDI (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.01-1.03). Early CDI was an independent significant predictor of death (HR, 1.96; 95% CI, 1.14-3.36) as well as CDI anytime after transplant (HR, 1.61; 95% CI, 1.02-2.52)., Conclusions: CDI rates varied widely from 2000 through 2011, with the highest rates in 2007 to 2008. Lung transplant recipients who developed CDI had a higher risk of death, especially when CDI occurred in the first 6 months after transplant., (© 2013 International Society for Heart and Lung Transplantation. All rights reserved.)

Background: Tacrolimus (FK506) has a superior immunosuppressive effect compared with cyclosporine (CSA) without a significant increase in generalized infectious complications. Differences in specific infections such as Clostridium difficile (CDI) have not been reported. We investigated the relationship between calcineurin inhibitors and CDI, hypothesizing that choice of calcineurin inhibitor (CSA or FK506) after lung transplantation would have no effect on the incidence of CDI., Methods: We performed a retrospective chart review of lung transplant recipients between June 1, 2000, and December 31, 2005, at a single institution. Positive CDI assays through December 11, 2011, were also recorded. We used Student's t- and chi-squared tests (α = 0.05) to compare CSA and FK506 groups. We calculated adjusted hazard ratios for CDI using Cox proportional hazard models., Results: We identified 217 lung transplant recipients: 106 patients in the CSA group and 111 patients in the FK506 group. A total of 31 patients (27.9%) in the FK506 group developed CDI postoperatively compared with 20 patients (18.9%) in the CSA group (P = 0.16). The adjusted hazard ratio for CDI in the FK506 group was not significantly higher (1.53; 95% confidence interval, 0.78-2.98). There was no significant difference in the intensive care unit or total length of stay, in-hospital incidence rate, time to first CDI episode, or recurrence rate between groups., Conclusions: The CDI rates were not significantly higher in the FK506 group than the CSA group in our study. These data are consistent with previous studies on FK506 that show no increase in infectious complications over CSA, and demonstrate its continued safety in lung transplantation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: Clostridium difficile infection (CDI) rates have been rising in recent years. We aimed to characterize CDI in lung transplant recipients in the modern era and hypothesized that CDI would increase the mortality risk., Methods: We performed a retrospective chart review of patients undergoing transplantation at our center from 1/2006 to 7/2011. Attributes of CDI+ and CDI- groups were compared using Student's t- and chi-square tests (α = 0.05). Multivariate Cox proportional hazard models were used to control for confounding factors., Results: Overall CDI incidence was 22.5%. Seven of 151 patients (4.6%) developed CDI during the initial hospitalization after transplantation (mean time 10.6 ± 6 d) while 27 patients (19.7%) developed CDI after discharge (mean time 467 ± 471 d). Incidence rate was 224.6 cases/100 000 patient-days compared to 110 cases/100 000 patient-days (rate for entire hospital). CDI was not predictive of mortality (HR 2.06, 95% CI 0.94-4.52)., Conclusion: CDI rates in lung transplant recipients are high in the modern era. No risk factors for CDI were identified. Although not statistically significant, CDI+ patients had a higher risk of death. The economic burden of CDI and trend toward worse outcomes for CDI patients have important implications for post-operative surveillance of CDI-related complications and need for CDI prophylaxis., (© 2013 John Wiley & Sons A/S.)

Objective: Functional endoscopic sinus surgery (FESS) provides symptomatic relief of sinus disease in patients with cystic fibrosis (CF), but it is unclear whether it has beneficial effects on lung disease in this population. This study assessed the effect of FESS on the respiratory status of adult patients with CF., Study Design: Retrospective chart review., Setting: Tertiary medical center., Subjects: Thirty-two adult patients with CF who underwent 45 operative cases., Methods: Clinical information retrieved for the 12-month periods preceding and following to determine the effect of FESS on the rate of decline in lung function, as well as intravenous antibiotic use and hospitalization for pulmonary exacerbation., Results: The rate of decline in forced expiratory volume in 1 second and forced vital capacity was not significantly different in the 12 months before and after FESS. Functional endoscopic sinus surgery did not reduce days hospitalized or days on intravenous antibiotics for a respiratory exacerbation in the pre- vs postoperative period. Limiting the analysis to the 30 surgeries that were performed in patients with concomitant respiratory symptoms (ie, excluding the 15 surgeries performed for sinus symptoms alone) did not significantly alter the results. Covariates of importance in CF, including CFTR genotype, gender, or microbiology, did not affect the study results., Conclusion: These results did not demonstrate an effect of FESS on progression of lung disease in patients with CF, but further research is needed because low statistical power has made some of the negative findings inconclusive.

Background: VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro., Methods: A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo., Results: The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens., Conclusions: In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit., Clinical Trial Number: NCT00865904.

Tracheobronchopathia osteochondroplastica (TO) is a rare large-airway disorder of unknown cause, characterized by the development of multiple submucosal osseous and/or cartilaginous nodules that protrude into the lumen of the trachea and large bronchi. Although most patients are asymptomatic, some may present with nonspecific respiratory symptoms. A chest computed tomographic scan with multiple protruding nodules in the trachea is suggestive but other diagnoses can present with a similar appearance; hence, definitive diagnosis may require bronchoscopic examination. Numerous cases of TO have been reported in association with different diseases, but no definitive causative explanation has been shown with any of the conditions. Chronic airway inflammation is one of the proposed mechanisms to explain the formation of TO nodules. Most of the reported TO patients have a history of frequent airway infections. Patients with IgA deficiency present with frequent sinopulmonary infections. The present case illustrates the first case of TO associated with IgA deficiency.

Post-transplant lymphoproliferative disorders (PTLD) are potentially fatal complications of solid organ transplantation. The natural history of PTLD varies considerably among the different types of organs transplanted. While lung transplant recipients are highly susceptible to PTLD, there are only a few small studies that detail PTLD in this setting. We undertook this study to better describe the characteristics and treatment response in PTLD after lung transplantation. We conducted a retrospective chart review of lung and heart/lung-transplant recipients between 1985 and 2008. A total of 32 cases (5%) of PTLD were identified in 639 patients. The median interval after transplantation to the diagnosis was 40 (3-242) months. Eight patients (25%) were diagnosed within one yr of transplantation and had PTLD predominantly within the thorax and allograft. Twenty-four patients (75%) were diagnosed more than one yr after transplantation and their tumors mainly affected the gastrointestinal tract. Monomorphic PTLD, diffuse large B-cell lymphoma, was diagnosed in 91%. Treatment of PTLD varied according to stage and clinical circumstances. Twenty-four patients (75%) have died. The median overall survival was 10 (0-108) months. PTLD after lung transplantation remains a challenge as a result of its frequency, complexity and disappointing outcome., (© 2010 John Wiley & Sons A/S.)

Background: A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro., Methods: We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study)., Results: At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was -3.5 mV (range, -8.3 to 0.5; P=0.02 for the within-subject comparison, P=0.13 vs. placebo), and the median change in the level of sweat chloride was -59.5 mmol per liter (range, -66.0 to -19.0; P=0.008 within-subject, P=0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P=0.008 for the within-subject comparison, P=0.56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770., Conclusions: This study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis. (Funded by Vertex Pharmaceuticals and others; ClinicalTrials.gov number, NCT00457821.).

Background: Gastroesophageal reflux (GER) in adults with cystic fibrosis (CF) is poorly characterized. This study examines the frequency and predictors of GER symptoms and their relationship to lung function in adults with CF., Methods: Cross-sectional study of adults at the University of Minnesota CF Clinic using two validated self report surveys: The Mayo GER questionnaire and the GERD Symptom Assessment Scale (GSAS)., Results: Of 274 invited patients, 201 (73%) completed the surveys and 173 performed spirometry at the same visit. Frequent symptoms (at least weekly) were reported by 24% of the patients and an additional 39% experienced occasional symptoms. Heartburn, acid regurgitation and dysphagia were the most common symptoms and 18% reported that GER symptoms worsened their respiratory condition. Females and patients reporting weight loss had more symptoms (mean GSAS symptom score 4.9 vs. 4.0, p=0.025 and 5.3 vs. 4.2, p=0.04) and more severe symptoms (mean GSAS distress score 5.6 vs. 3.8, p=0.005 and 6.8 vs. 4.0, p=0.01) compared to males and those who did not report weight loss. Patients on acid suppression (n=122, 61%) continued to report heartburn (n=80, 66%) and acid regurgitation (n=47, 23%). GER symptoms and severity of symptoms were not predictive of FEV(1) or FVC., Conclusions: GER symptoms were present in a majority of patients. Females and patients with weight loss require special attention to their GER symptoms. Many patients on acid suppression continued to be report symptoms., (Copyright © 2010 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of transplantation. We examined the role of positron emission tomography (PET) scanning in PTLD., Methods: All patients treated for PTLD from 2001-2006 who also underwent PET scans were reviewed., Results: Nineteen PTLD patients were included. Seventeen patients had PET scans for staging at diagnosis. Of these, two patients with primary central nervous system lymphoma and one patient with only bone marrow involvement after complete surgical resection of a bowel lesion had no abnormalities on CT or PET scan. The remaining patients had measurable, extracranial disease by CT scan and PET scan. The median maximum standard uptake value was 8.2 (range 3-30). Thirteen patients had a PET scan following treatment. Eleven of 13 patients had a complete response (CR). Two of 13 patients had persistent disease following therapy; in one of these patients, relapsed disease was documented by PET scan alone. Of the 11 patients with CR, three patients relapsed shortly thereafter. In each case, at the time of relapse, the PET scan confirmed recurrent disease regardless of histopathologic subtype., Conclusions: PET scans may have a role in the staging and follow-up of patients with PTLD. Additional prospective studies are warranted.

Pulmonary vein thrombosis is a serious complication of lung transplantation. Thrombus formation at the pulmonary venous anastomosis site may result in allograft failure and ischemic stroke. The optimal therapy is not known; open embolectomy and non-surgical management with or without anti-coagulation have been tried with variable success. We report a case of pulmonary vein thrombosis in a 31-year-old woman, presenting with sudden hemiparesis 24 days after lung transplantation.

Background: Gastroesophageal reflux disease (GERD) is common in a variety of chronic respiratory diseases, but little is known about GERD in the setting of COPD. The aims of this study were to determine the prevalence, presentation, and predictors of GERD based on proximal and distal esophageal pH monitoring in patients with severe COPD., Methods: Forty-one COPD patients with a mean FEV1 of 24% of predicted underwent dual-probe 24-h esophageal pH monitoring, and 1 patient underwent esophagogastroduodenoscopy., Results: The prevalence of GERD was 57%. Elevated distal and proximal reflux were present in 41% and 46% of patients undergoing esophageal pH studies, respectively. Fifteen percent of these patients had abnormal proximal reflux despite having normal distal probe results. Most patients with GERD were not receiving acid blockers at the time of their referral, and only one third reported heartburn and/or acid regurgitation during the pH study. Only higher body mass index was predictive of reflux on regression analysis (odds ratio, 1.2; 95% confidence interval, 1.0 to 1.5; p = 0.05)., Conclusions: GERD is common in advanced COPD. Patients are often asymptomatic and have a relatively high prevalence of isolated abnormal proximal reflux. Dual-probe monitoring is therefore well suited for detecting GERD in patients with advanced COPD.

Background: Idiopathic pulmonary fibrosis (IPF) is the second largest indication for lung transplantation worldwide. Average 90-day mortality rates for this procedure are 22%. It is unclear what factors predispose patients with IPF to this increased early posttransplant mortality. Pulmonary hypertension may increase the risk of development of early posttransplant complications through several mechanisms. We examined the effect of secondary pulmonary hypertension on 90-day mortality after lung transplantation for IPF., Methods: An International Society for Heart and Lung Transplant Registry cohort study of 830 patients with IPF transplanted from January 1995 to June 2002 was undertaken. Risk factors were assessed individually and adjusted for confounding by a multivariable logistic regression model., Results: In the univariate analysis, pulmonary hypertension and bilateral-lung transplantation were significant risk factors for increased 90-day mortality. Multivariate analysis confirmed that mean pulmonary artery pressure and bilateral procedure remain independent risk factors after adjustment for potential confounders. Recipient age, ischemia time, cytomegalovirus status mismatch, and donor age were not independent risk factors for early mortality., Conclusions: Bilateral-lung transplantation carries a greater risk of early mortality than single-lung transplantation for IPF. Increasing pulmonary artery pressure is a risk factor for death after single-lung transplantation in IPF. Mean pulmonary artery pressure should be included in the overall risk assessment of patients with IPF evaluated for lung transplantation.

Goal: The goal of this study was to assess the efficacy of sirolimus in lung-transplant recipients., Methods: The study was designed as a single center, consecutive case study of lung-transplant recipients treated with sirolimus, tacrolimus, and prednisone. All study subjects also received an HMG-CoA reductase inhibitor, and prophylaxis for cytomegalovirus and Pneumocystis carinii., Results: A total of 15 subjects were enrolled in the study. Within 6 months, significant airway complications occurred in four subjects, three of whom died. At that point, the investigators terminated enrollment in the study. The study population was compared retrospectively with a group of 83 consecutive lung recipients treated with cyclosporine (n=64) or tacrolimus (n=19), mycophenolate mofetil, and prednisone. This confirmed an increased incidence of airway dehiscence and reduced survival in the sirolimus-treated patients. Sirolimus-treated patients had a low incidence of acute rejection. No significant differences were noted in the incidence of bacterial or fungal bronchopulmonary infections., Conclusions: We observed an unexpectedly high incidence of postoperative airway dehiscence in lung-transplant recipients treated with sirolimus, in combination with tacrolimus, prednisone, and an HMG-CoA inhibitor. Further studies will be needed to determine the safety and efficacy of using sirolimus after complete airway healing has occurred.

Background: RAD is a novel macrolide with potent immunosuppressive and antiproliferative activities. This study characterizes the safety, tolerability, and pharmacokinetics of two different single oral doses of RAD in stable lung and heart/lung transplant recipients with and without cystic fibrosis (CF)., Methods: This was a Phase I, multicenter, randomized, double-blind, two-period, two-sequence, crossover study. Single doses of RAD capsules at doses of 0.035 mg/kg (2.5 mg maximum) or 0.10 mg/kg (7.5 mg maximum) were administered with cyclosporine (Neoral [cyclosporine, USP] modified), steroids, and azathioprine on Day 1. The alternate dose was administered on Day 16. Laboratory assessments, vital signs, and adverse events were recorded throughout the study. RAD pharmacokinetic profiles were assessed over a 7-day period following each dose. Steady-state cyclosporine (CsA) profiles were assessed at baseline and with each RAD dose; RAD and CsA trough concentrations were obtained throughout the study period., Results: Of the 20 patients randomized, 8 had CF and 12 did not. Single doses of RAD were safe and well tolerated. Headache was the most common side effect. RAD produced a mild, dose-dependent, reversible decrease in platelet and leukocyte counts. Cholesterol and triglycerides were minimally affected. At both doses, CF patients had significantly lower peak concentrations of RAD than did non-CF patients (p = 0.03); however, overall exposure (area under the curve/dose) was not different between the groups (p = 0.63). At the higher dose, there was a clinically minor under-proportionality in AUC, averaging -11%. Steady-state pharmacokinetics of CsA were not affected by RAD co-administration.RAD was safe and well tolerated by stable lung and heart/lung transplant recipients with and without CF. The presence of CF did not influence the extent of RAD exposure. Single doses of RAD did not affect the pharmacokinetics of CsA. Ongoing studies are assessing the long-term safety and efficacy of RAD in lung and heart/lung transplantation.

7 days) failure. Seven (78%) patients in the early group were weaned off ECMO and 5 (56%) survived to hospital discharge. In the late group, none of the patients could be weaned off ECMO, yielding 100% mortality. ECMO support instituted for pulmonary graft failure that occurred within 24 hours of transplantation may improve patient survival.

In many diseases the lung is injured by oxidants. gamma-Glutamyl transpeptidase (GGT) is an ectoenzyme on the apical plasma membrane of many epithelial cells that protects against oxidants by replenishing intracellular glutathione. We sought to localize GGT within rat lungs in vivo and in cultured alveolar epithelial cells. In the adult rat lung, indirect immunofluorescence (IF) with a polyclonal antibody to triton-solubilized GGT revealed linear staining outlining the alveoli. Immunoelectron microscopy (IEM) localized the protein on the apical surface of the alveolar epithelial cells, but more densely on type I cells than type II cells, as well as on the apical surface of some ciliated bronchial cells. On Western blots of whole lung and isolated type II cell membrane proteins, the antibody predominantly recognized a broad protein band of 110-120 kDa, consistent with the uncleaved, glycosylated form of GGT. Over time in culture, isolated rat type II cells had increasing immunoreactivity on Western blots and indirect IF but decreasing enzyme activity. At 2 days in culture, confocal laser scanning microscopy demonstrated that GGT was polarized to the apical surface of nonconfluent type II cells. Thus GGT is a polarized apical membrane protein in type I and II cells, suggesting a role in the metabolic functions of these cells. The increased immunoreactive GGT of cultured type II cells is consistent with their acquisition of properties similar to type I cells, but the lack of correlation between immunoreactive protein and enzyme activity awaits explanation.