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Background: Previous studies of patients with bronchiectasis have found that the cause is idiopathic in the majority of cases, but these studies were done in homogeneous populations. We hypothesized that the etiology of bronchiectasis can be determined in a higher percentage of patients in a diverse US population and will differ significantly based on ethnicity.Methods: One hundred twelve patients with bronchiectasis confirmed by chest CT scan entered the study. Data from 106 patients were available for full evaluation. Clinical questionnaire, pulmonary function tests, sputum microbiology, laboratory data, and immune function testing were done. Results were analyzed by ethnicity and etiology.Results: Patients were 61.6% European American (EA), 26.8% African American (AA), 8.9% Hispanic American (HA), and 2.7% Asian American. A cause of bronchiectasis was determined in 93.3% of patients. In 63.2% of patients, bronchiectasis was caused by immune dysregulation, including deficiency (n = 18 [17%]), autoimmune disease (n = 33 [31.1%]), hematologic malignancy (n = 15 [14.2%]), and allergic bronchopulmonary aspergillosis (n = 1 [0.9%]). Rheumatoid arthritis was the cause of bronchiectasis in 28.6% of AA patients vs 6.2% of EA patients (P < .05). Hematologic malignancy was the etiology in 20.0% of the EA patients vs none of the AA patients (P = .02). A significantly higher percentage of HA patients had Pseudomonas aeruginosa in their sputum compared with AA and EA patients (P = .01).Conclusions: The etiology of bronchiectasis can be determined in the majority of patients in a heterogeneous US population and is most often due to immune dysregulation. Rheumatoid arthritis is more likely in AA patients than EA patients. HA patients are more likely to have P aeruginosa in their sputum. [ABSTRACT FROM AUTHOR]

Persistent neutrophilic inflammation is a central feature in both the pathogenesis and progression of bronchiectasis (BE). Neutrophils release neutrophil serine proteases (NSPs), such as neutrophil elastase, cathepsin G and proteinase 3. When chronically high levels of free NSP activity exceed those of protective antiproteases, structural lung destruction, mucosal-related defects, further susceptibility to infection and worsening of clinical outcomes can occur. Despite the defined role of prolonged, high levels of NSPs in BE, no drug that controls neutrophilic inflammation is licensed for the treatment of BE. Previous methods of suppressing neutrophilic inflammation (such as direct inhibition of neutrophil elastase) have not been successful; however, an emerging therapy designed to address neutrophil-mediated pathology, inhibition of the cysteine protease cathepsin C (CatC, also known as dipeptidyl peptidase 1), is a promising approach to ameliorate neutrophilic inflammation, since this may reduce the activity of all NSPs implicated in BE pathogenesis, and not just neutrophil elastase. Current data suggest that CatC inhibition may effectively restore the protease-antiprotease balance in BE and improve disease outcomes as a result. Clinical trials for CatC inhibitors in BE have reported positive Phase III results. In this narrative review, we discuss the role of high NSP activity in BE, and how this feature drives the associated morbidity and mortality seen in BE. This review discusses therapeutic approaches aimed at treating neutrophilic inflammation in the BE lung, summarising clinical trial outcomes, and highlighting the need for more treatment strategies that effectively address chronic neutrophilic inflammation in BE., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Bronchiectasis is characterised by uncontrolled neutrophil serine protease (NSP) activity. Cathepsin C (CatC; dipeptidyl peptidase 1) activates NSPs during neutrophil maturation. CatC inhibitors can potentially reduce neutrophil-mediated lung damage. This Phase II, randomised, double-blind, placebo-controlled trial (AIRLEAF®; NCT05238675) evaluated efficacy, safety and optimal dosing of BI 1291583, a novel, reversible CatC inhibitor, in adults with bronchiectasis.In total, 322 participants were randomised (2:1:1:2) to receive one of three oral doses of BI 1291583 (1 mg/2.5 mg/5 mg) or placebo for 24 to 48 weeks. A multiple comparison procedure and modelling approach was used to demonstrate a non-flat dose-response curve based on the time to first pulmonary exacerbation up to Week 48. In addition, efficacy of individual BI 1291583 doses was evaluated based on the frequency of exacerbations, severe exacerbations (fatal or leading to hospitalisation and/or intravenous antibiotic administration), lung function and quality of life.A significant dose-dependent benefit of BI 1291583 over placebo was established based on time to first exacerbation (shape: Emax; adjusted p-value: 0.0448). Treatment with BI 1291583 5 mg and 2.5 mg numerically reduced the risk of an exacerbation compared with placebo (hazard ratios: 0.71 and 0.66, 95% CIs 0.48-1.05 and 0.40-1.08; both p>0.05). BI 1291583 2.5 mg showed numerically better efficacy compared with 5 mg across several endpoints; 1 mg was similar to placebo. The safety profile of BI 1291583 was similar to placebo.Treatment with BI 1291583 resulted in a reduction in the risk of experiencing an exacerbation in adults with bronchiectasis., (Copyright ©The authors 2024.)

Background: The overall burden of bronchiectasis on patients and healthcare systems has not been comprehensively described. Here, we present the findings of a systematic literature review that assessed the clinical and socioeconomic burden of bronchiectasis with subanalyses by aetiology (PROSPERO registration: CRD42023404162)., Methods: Embase, MEDLINE and the Cochrane Library were searched for publications relating to bronchiectasis disease burden (December 2017-December 2022). Journal articles and congress abstracts reporting on observational studies, randomised controlled trials and registry studies were included. Editorials, narrative reviews and systematic literature reviews were included to identify primary studies. PRISMA guidelines were followed., Results: 1585 unique publications were identified, of which 587 full texts were screened and 149 were included. A further 189 citations were included from reference lists of editorials and reviews, resulting in 338 total publications. Commonly reported symptoms and complications included dyspnoea, cough, wheezing, sputum production, haemoptysis and exacerbations. Disease severity across several indices and increased mortality compared with the general population was reported. Bronchiectasis impacted quality of life across several patient-reported outcomes, with patients experiencing fatigue, anxiety and depression. Healthcare resource utilisation was considerable and substantial medical costs related to hospitalisations, treatments and emergency department and outpatient visits were accrued. Indirect costs included sick pay and lost income., Conclusions: Bronchiectasis causes significant clinical and socioeconomic burden. Disease-modifying therapies that reduce symptoms, improve quality of life and reduce both healthcare resource utilisation and overall costs are needed. Further systematic analyses of specific aetiologies and paediatric disease may provide more insight into unmet therapeutic needs., Competing Interests: Conflict of interest: The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed and Trudell, and received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon. M.A. Mall reports research grants paid to their institution from the German Research Foundation (DFG), German Ministry for Education and Research (BMBF), German Innovation Fund, Vertex Pharmaceuticals and Boehringer Ingelheim; consultancy fees from AbbVie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Santhera, Splisense and Vertex Pharmaceuticals; speaker fees from Vertex Pharmaceuticals; and travel support from Boehringer Ingelheim and Vertex Pharmaceuticals. M.A. Mall also reports advisory board participation for AbbVie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari and Vertex Pharmaceuticals and is a fellow of ERS (unpaid). P.J. McShane is an advisory board member for Boehringer Ingelheim's Airleaf trial and Insmed's Aspen trial. P.J. McShane is also a principal investigator for clinical trials with the following pharmaceutical companies: Insmed: Aspen, 416; Boehringer Ingelheim: Airleaf; Paratek: oral omadacycline; AN2 Therapeutics: epetraborole; Renovian: ARINA-1; Redhill; Spero; and Armata. K.G. Nielsen reports advisory board membership for Boehringer Ingelheim. M. Shteinberg reports having received research grants from Novartis, Trudell Pharma and GlaxoSmithKline; travel grants from Novartis, Actelion, Boehringer Ingelheim, GlaxoSmithKline and Rafa; speaker fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Insmed, Teva, Novartis, Kamada and Sanofi; and advisory fees (including steering committee membership) from GlaxoSmithKline, Boehringer Ingelheim, Kamada, Syncrony Medical, Zambon and Vertex Pharmaceuticals. M. Shteinberg also reports data and safety monitoring board participation for Bonus Therapeutics, Israel and is an ERS Task Force member on bronchiectasis guideline development. S.D. Sullivan has participated in advisory boards for Boehringer Ingelheim and has research grants from Pfizer, Bayer and GlaxoSmithKline. S.H. Chotirmall is on advisory boards for CSL Behring, Boehringer Ingelheim and Pneumagen Ltd, served on a data and safety monitoring board for Inovio Pharmaceuticals Inc., and has received personal fees from AstraZeneca and Chiesi Farmaceutici., (Copyright ©The authors 2024.)

Rationale: Nontuberculous mycobacteria (NTM) are prevalent among patients with bronchiectasis. However, the long-term natural history of patients with NTM and bronchiectasis is not well described. Objectives: To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis. Methods: Patients in the Bronchiectasis and NTM Research Registry with ⩾5 years of follow-up were eligible. Data were collected for all-cause mortality, lung function, exacerbations, hospitalizations, and disease severity. Outcomes were compared between patients with and without NTM at baseline. Mortality was assessed using Cox proportional hazards models and the log-rank test. Measurements and Main Results: In total, 2,634 patients were included: 1,549 (58.8%) with and 1,085 (41.2%) without NTM at baseline. All-cause mortality (95% confidence interval) at Year 5 was 12.1% (10.5%, 13.7%) overall, 12.6% (10.5%, 14.8%) in patients with NTM, and 11.5% (9.0%, 13.9%) in patients without NTM. Independent predictors of 5-year mortality were baseline FEV 1 percent predicted, age, hospitalization within 2 years before baseline, body mass index, and sex (all P  < 0.01). The probabilities of acquiring NTM or Pseudomonas aeruginosa were approximately 4% and 3% per year, respectively. Spirometry, exacerbations, and hospitalizations were similar, regardless of NTM status, except that annual exacerbations were lower in patients with NTM ( P  < 0.05). Conclusions: Outcomes, including exacerbations, hospitalizations, rate of loss of lung function, and mortality rate, were similar across 5 years in patients with bronchiectasis with or without NTM.

Background: Drug susceptibility testing (DST) protocol of omadacycline against non-tuberculous mycobacteria has not yet been established. We developed a method to accurately determine MIC omadacycline MIC against Mycobacterium abscessus (Mab), Mycobacterium avium-complex (MAC), and Mycobacterium kansasii (Mkn)., Methods: First, we identified the oxyrase concentration not affecting Mab, MAC, and Mkn growth followed by omadacycline MIC experiments with and without oxyrase using reference and clinical strains., Results: Oxyrase 0.5 % (v/v) stabilized omadacycline in the culture medium. The median omadacycline MIC was 1 mg/L for Mab and 8 mg/L for Mkn. For MAC, the median omadacycline MIC was 2 mg/L for M. avium, 256 mg/L for M. intracellulare, and 4 mg/L for M. chimaera (p < 0.0001). Wilcoxon matched-pairs signed rank test revealed statistically lower MICs with oxyrase for all MAC subspecies (p < 0.0001), all Mab subspecies (p < 0.0001), and Mkn (p = 0.0002). The decrease in MICs with oxyrase was 17/18 of Mab, 14/19 of Mkn, 8/8 of M. avium, 4/5 M. chimera, but only 11/18 of M. intracellulare (p < 0.013)., Conclusion: Use of 0.5 % oxyrase could be a potential solution to reliable and reproducible omadacycline MIC of Mab. However, oxyrase demonstrated a variable effect in reducing MICs against MAC and Mkn., Competing Interests: Declaration of competing interest Tawanda Gumbo founded and is president and CEO of Praedicare Inc., a System of Systems Drug Development company, and founded Praedicare Africa, a clinical contract research organization. Julie V Philley is an advisor for Insmed, Paratek and AN2; a research investigator for Insmed, Paratek, AN2 and Zambon. All other authors have nothing to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Formerly regarded as a rare disease, bronchiectasis is increasingly recognised. A renewed interest in this disease has led to significant progress in bronchiectasis research. Randomised clinical trials (RCTs) have demonstrated the benefits of airway clearance techniques, inhaled antibiotics and long-term macrolide therapy in bronchiectasis patients. However, the heterogeneity of bronchiectasis remains one of the most challenging aspects of management. Phenotypes and endotypes of bronchiectasis have been identified to help find "treatable traits" and partially overcome disease complexity. The goals of therapy for bronchiectasis are to reduce the symptom burden, improve quality of life, reduce exacerbations and prevent disease progression. We review the pharmacological and non-pharmacological treatments that can improve mucociliary clearance, reduce airway inflammation and tackle airway infection, the key pathophysiological features of bronchiectasis. There are also promising treatments in development for the management of bronchiectasis, including novel anti-inflammatory therapies. This review provides a critical update on the management of bronchiectasis focusing on treatable traits and recent RCTs., Competing Interests: Conflict of interest: H. Choi reports grants from the Basic Science Research Program of the Korean Ministry of Education (grant number 2021R1I1A3052416), and consulting and lecture fees from Boryung Pharmaceutical Co., Ltd and Kolon Pharma. P.J. McShane reports study funding (paid to institution) from Boehringer Ingelheim, Armata, Paratek, Renovian, Spero, AN2 Therapeutics and Insmed, and speaker fees from Insmed. S. Aliberti reports grants or contracts from Insmed Incorporated, Chiesi, Fisher & Paykel and GlaxoSmithKline, royalties or licences from McGraw Hill, consulting fees from Insmed Incorporated, Insmed Italy, Insmed Ireland Ltd, Zambon SpA, AstraZeneca UK Ltd, AstraZeneca Pharmaceutical LP, CSL Behring GmbH, Grifols, Fondazione Internazionale Menarini, Moderna, Chiesi, MSD Italia Srl, Brahms, Physioassist SAS and GlaxoSmithKline SpA, payment or honoraria for lectures, presentations, manuscript writing or educational events from GlaxoSmithKline SpA, Thermofisher Scientific, Insmed Italy, Insmed Ireland, Zambon and Fondazione Internazionale Menarini, and participation on a data safety monitoring board or advisory board for Insmed Incorporated, Insmed Italy, AstraZeneca UK Ltd and MSD Italia Srl. J.D. Chalmers reports grants or contracts from AstraZeneca, Boehringer Ingelheim, Genentech, Gilead Sciences, GlaxoSmithKline, Grifols, Insmed, LifeArc and Novartis, and consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, Insmed, Grifols, Novartis, Boehringer Ingelheim, Pfizer, Janssen, Antabio and Zambon., (Copyright ©The authors 2024.)

Patients with nontuberculous mycobacterial (NTM) lung infection require life-long attention to their bronchiectasis, whether or not their NTM infection has been cured. The identification of the cause of bronchiectasis and/or coexisting diseases is important because it may affect therapeutic strategies. Airway clearance is the mainstay of bronchiectasis management. It can include multiple breathing techniques, devices, and mucoactive agents. The exact airway clearance regimen should be customized to each individual patient. Chronic pathogenic airway bacteria, such as Pseudomonas aeruginosa, may warrant consideration of eradication therapy and/or chronic use of maintenance inhaled antibiotics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rationale: Longitudinal epidemiological and clinical data are needed to improve the management of patients with bronchiectasis developing nontuberculous mycobacterial (NTM) pulmonary disease., Objectives: To describe the epidemiology, patient management, and treatment outcomes of NTM infections in patients with bronchiectasis enrolled in the United States Bronchiectasis and NTM Research Registry (US BRR)., Methods: This was a retrospective cohort study of patients with bronchiectasis and NTM infections enrolled with follow-up in the US BRR in 2008-2019. The study included patients with ≥1 positive NTM respiratory culture in the 24-month baseline period (baseline NTM cohort) and/or during the annual follow-up visits (incident NTM cohort). Incidence, prevalence, baseline patient characteristics, treatment exposure, treatment outcomes, and respiratory clinical outcomes were described in the baseline NTM cohort, incident NTM cohort, and both cohorts combined (prevalent NTM cohort)., Results: Between 2008 and 2019, 37.9% (1457/3840) of patients with bronchiectasis in the US BRR met the inclusion criteria for this study and were reported to have Mycobacterium avium complex (MAC) and/or Mycobacterium abscessus complex (MABSC) infections. MAC prevalence increased steadily in the US BRR during 2009-2019; incidence was relatively stable, except for a peak in 2011 followed by a slow decrease. MABSC and mixed MAC/MABSC infections were rare. Most patients with bronchiectasis and NTM infections in the registry were female, White, and aged >65 years. The antibiotics administered most commonly reflected current guidelines. In the prevalent cohort, 44.9% of MAC infections and 37.1% of MABSC infections remained untreated during follow-up, and MAC treatment was initiated with delay (>90 days after positive NTM respiratory culture) twice as frequently as promptly (≤90 days after positive NTM respiratory culture) (68.6% vs 31.4%, respectively). The median time from diagnosis to treatment was shorter for MABSC versus MAC infections (194.0 days [interquartile range (IQR) 8.0, 380.0] vs 296.0 days [IQR 35.0, 705.0], respectively). Among patients with MAC infections who completed treatment, 27.6% were classified as cured and 29.6% as treatment failure during the annual follow-up visit window. For MABSC, these proportions were 25.0% and 28.0%, respectively., Conclusions: A considerable proportion of MAC and MABSC infections were untreated or treated after initial delay/observation. MABSC infections were more likely to be treated and start treatment sooner than MAC infections. Further longitudinal studies are warranted to evaluate the monitor-with-delay approach and inform clinical guidelines., Competing Interests: Declaration of competing interest MD, HS, IG, ST, SS: employees of GSK and GSK shareholders at the time of this study; all GSK employees were involved in the study design, decision to publish, data analysis and interpretation, and preparation of the manuscript. ST: scientific liaison officer of The Union; deputy editor of the International Journal of Tuberculosis and Lung Disease. CS: speaker fees from Insmed. DM: consulting fees from AstraZeneca and COPD Foundation; honoraria from Medscape; payment for expert testimony from Schlesinger Law Firm; stock or stock options with GSK and Johnson and Johnson. MM: advisory board, grants, and consulting fees from Insmed. NL: grants for educational projects and conference travel fees from Insmed. PMS: grants as primary investigator for clinical trials from AN2 Therapeutics, Boehringer Ingelheim, Electromed, Hillrom, Insmed, Parateck, RedHill Biopharma, and Revovion; honorarium for steering committee from Insmed; speaker fees for Arikayce from Insmed. KW: grants and/or consulting fees from AN2, Insmed, Paratek, Renovion, RedHill Biopharma, and Vast; advisory board fees from RedHill Biopharma., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Guideline-based therapy (GBT) for pulmonary Mycobacterium abscessus (Mab) disease achieves sustained sputum culture conversion (SSCC) rates of 30%; this is reflected by poor efficacy of GBT in the hollow fiber system model of Mab (HFS-Mab), which killed ∼1.22 log 10 CFU/mL. This study was performed to determine which clinical dose of omadacycline, a tetracycline antibiotic, should be used in combination therapy to treat pulmonary Mab disease for relapse-free cure., Methods: First, omadacycline intrapulmonary concentration-time profiles of seven daily doses were mimicked in the HFS-Mab model and exposures associated with optimal efficacy were identified. Second, 10,000 subject Monte-Carlo simulations were performed to determine whether oral omadacycline 300 mg/day achieved these optimal exposures. Third, a retrospective clinical study on omadacycline vs. primarily tigecycline-based salvage therapy was conducted to assess rates of SSCC and toxicity. Fourth, a single patient was recruited to validate the findings., Results: Omadacycline efficacy in the HFS-Mab was 2.09 log 10 CFU/mL at exposures achieved in >99% of patients on 300 mg/day omadacycline. In the retrospective study of omadacycline 300 mg/day-based combinations vs. comparators, SSCC was achieved in 8/10 vs. 1/9 (P=0.006), symptom improvement in 8/8 vs. 5/9 (P=0.033), toxicity in 0 vs. 9/9 (P<0.001), and therapy discontinuation due to toxicity in 0 vs. 3/9 (P<0.001) cases, respectively. In one prospectively recruited patient, omadacycline 300 mg/day salvage therapy achieved SSCC and symptom-resolution in 3 months., Conclusion: Based on the preclinical and clinical data, omadacycline 300 mg/day in combination regimens could be appropriate for testing in Phase III trials in patients with Mab pulmonary disease., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Competing Interests: SHC has received research grants from the Singapore Ministry of Health's National Medical Research Council and National Research Foundation and is on advisory boards for CSL Behring, Pneumagen, and Boehringer Ingelheim, has served on Data and Monitoring Boards (DSMB) for Inovio Pharmaceuticals, and has received personal fees from AstraZeneca and Chiesi Farmaceutici, all outside of the submitted work. RD has received grants from Glenmark and CIPLA, consulting fees from CIPLA, LUPIN, and Pfizer and personal fees from CIPLA, LUPIN, Glenmark, SUN Pharma, Pfizer, Glaxo Smith Kline, Sanofi, Zydus, and German Remedies, outside of the submitted work. PJM is primary site investigator for clinical trials sponsored by Insmed and Boehringer Ingelheim and has received consulting fees from Boehringer Ingelheim. ABC has received grants from the Australian National Health and Medical Research Council, royalties from UptoDate, support from the European Respiratory Society for travel, and served on DSMB for AstraZeneca, Glaxo Smith Kline, and Moderna.

New therapies are needed to prevent exacerbations, improve quality of life and slow disease progression in bronchiectasis. Inhibition of cathepsin C (CatC) activity has the potential to decrease activation of neutrophil-derived serine proteases in patients with bronchiectasis, thereby reducing airway inflammation, improving symptoms, reducing exacerbations and preventing further airway damage. Here we present the design of a phase 2 trial (Airleaf™; NCT05238675) assessing the efficacy and safety of a novel CatC inhibitor, BI 1291583, in adult patients with bronchiectasis. This multinational, randomised, double-blind, placebo-controlled, parallel-group, dose-finding study has a screening period of at least 6 weeks, a treatment period of 24-48 weeks and a follow-up period of 4 weeks. ∼240 adults with bronchiectasis of multiple aetiologies will be randomised to placebo once daily, or BI 1291583 1 mg once daily, 2.5 mg once daily or 5 mg once daily in a 2:1:1:2 ratio, stratified by Pseudomonas aeruginosa infection and maintenance use of macrolides. The primary efficacy objective is to evaluate the dose-response relationship for the three oral doses of BI 1291583 versus placebo on time to first pulmonary exacerbation up to Week 48 (the primary end-point). Efficacy will be assessed using exacerbations, patient-reported outcomes, measures of symptoms, sputum neutrophil elastase activity and pulmonary function testing. Safety assessment will include adverse event reporting, physical examination, monitoring of vital signs, safety laboratory parameters, 12-lead electrocardiogram, and periodontal and dermatological assessments. If efficacy and safety are demonstrated, results will support further investigation of BI 1291583 in phase 3 trials., Competing Interests: Conflict of interest: J.D. Chalmers reports grants from GSK, Boehringer Ingelheim, Zambon, Insmed, Grifols, Novartis, Gilead and AstraZeneca, and is an associate editor of this journal. A. Gupta, A. Eleftheraki, C. Diefenbach and W. Sauter are employees of Boehringer Ingelheim International GmbH. S.H. Chotirmall reports grants paid to his institution from the Singapore Ministry of Health's National Medical Research Council under its Clinician-Scientist Individual Research Grant (MOH-000141), Clinical-Scientist Award (MOH-000710) and National Research Foundation Singapore under its COVID-19 Research Fund administered by the Singapore Ministry of Health's National Medical Research Council (MOH-000409), consulting fees from CSL Behring, Pneumagen Ltd and Boehringer Ingelheim, lecture fees from AstraZeneca, and participation in Data Safety and Monitoring Committees for Inovio Pharmaceuticals and Imam Abdulrahman Bin Faisal University. A. Armstrong reports consulting fees from AbbVie, Almirall, Arcutis, ASLAN, Beiersdorf, BMS, Dermavant, EPI, Incyte, Nimbus, Dermira, Eli Lilly, Janssen, Leo Pharma, Modernizing Medicine, Novartis, Ortho Dermatologics, Regeneron, Sanofi Genzyme, Sun Pharma, UCB Pharma, Boehringer Ingelheim, Parexel and Pfizer, payment or honoraria from AbbVie, ASLAN, Boehringer Ingelheim, BMS, EPI, Incyte, Leo, UCB, Janssen, Lilly, Novartis, Ortho Dermatologics, Sun, Dermavant, Dermira, Sanofi Regeneron, Parexel, Pfizer, Almirall, Arcutis, Nimbus and ModMed, participation on advisory boards for Boehringer Ingelheim and Parexel, and is on the board of directors for the American Academy of Dermatology. P. Eickholz reports payment or honoraria for lectures from Boehringer Ingelheim, Sanofi Aventis, Kulzer, CP GABA and Philips, and lectures primarily in the dental field. N. Hasegawa reports grants for a clinical trial and consulting fees from Insmed. P.J. McShane reports study funding to her institution from Boehringer Ingelheim and speaker fees from Insmed. A.E. O'Donnell reports grants for study funding from Insmed, AstraZeneca, Zambon and the US Bronchiectasis Research Registry, consulting fees from Insmed, Boehringer Ingelheim, Zambon, Electromed, AstraZeneca and Xellia, payment for CME from Vindico Medical Education, participation in a Data Safety Monitoring Board for Parexel, and a role with the US Bronchiectasis Research Registry. M. Shteinberg reports grants paid to her institution from GSK, Trumed and Novartis, consulting fees from GSK, Boehringer Ingelheim, Kamada, Zambon and Vertex, payment or honoraria from Boehringer Ingelheim, GSK, AstraZeneca, Teva, Novartis and Kamada, support for attending meetings from Novartis, Actelion, Boehringer Ingelheim, GSK and Rafa, participation on advisory boards from Bonus Therapeutics (Israel), unpaid fiduciary roles for EMBARC Management and the Israel Pulmonology Society Board, and receipt of supply to a clinical trial from Trudell. H. Watz has nothing to disclose., (Copyright ©The authors 2023.)

Demographic and socioeconomic factors are recognized to contribute to disparities in healthcare outcomes. Originally, bronchiectasis was described in a population of predominantly White ethnic group of patients in which racial disparity could not be identified. The U.S. Bronchiectasis Research Registry (BRR), a centralized database of adult patients with bronchiectasis and/or NTM from 18 clinical institutions across the U.S., was created to support the research of this condition. The aim of this study is to describe the racial and ethnic distribution of patients enrolled in the BRR and evaluate factors associated with healthcare disparities within manifestations of and/or the care delivered to this population. At the time of this study, 3600 patients with bronchiectasis and/or NTM were enrolled in the BRR. Of those, 3510 participants were included in these analyses. The population was predominantly non-HispanicWhite (n = 3143, 89.5%), followed by Hispanic or Latino (n = 149, 4.3%), Asian (n = 130, 3.7%) and non-Hispanic Black (n = 88, 2.5%) participants. Testing for cystic fibrosis, immunoglobulin deficiency, and mycobacteria was not different between races, but non-Hispanic Black patients were tested less frequently for alpha-1 antitrypsin (A1AT) deficiency compared to other groups (P = 0.01). The four groups did not differ in the proportion of Pseudomonas aeruginosa or Hemophilus influenzae. There was no statistically significant difference in use of high-frequency chest wall oscillation, pulmonary rehabilitation services, or suppressive macrolide treatment across the groups (P > 0.05). There is a disproportionately high percentage of non-Hispainc White patients compared to non-Hispanic Black patients and Hispanic or Latino patients in the BRR. However, we found an overall similarity of care of BRR patients, regardless of racial and ethnic group., Competing Interests: Declaration of competing interest The authors declare no financial relationships, compensation or intellectual property related to the work in this manuscript., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Little information is available about Stenotrophomonas maltophilia in patients with bronchiectasis. We analyzed data from the US Bronchiectasis and NTM Research Registry to determine its prevalence and association with patient characteristics and severity of disease., Methods: Baseline and follow-up data were entered into a central web-based database. Patients were grouped into four cohorts based on their baseline cultures: 1) S. maltophilia, no Pseudomonas aeruginsosa, 2) P. aeruginosa, no S. maltophilia, 3) No pathogens, 4) Pathogens other than P. aeruginosa and S. maltophilia. The association between S. maltophilia, demographic characteristics, pulmonary function, exacerbations and hospitalizations was assessed at baseline and one year follow-up., Results: Among 2659 patients, 134 (5.0%) had grown S. maltophilia at baseline. The prior exacerbation rate at baseline was similar in patients with S. maltophilia and P. aeruginosa, but significantly higher than the other two groups. Hospitalizations were more frequent in patients with S. maltophilia or P. aeruginosa. Pre-bronchodilator FEV1 among S. maltophilia patients was between that of Pseudomonas patients and patients without either organism, but was not significantly different from any of the other groups. For all risk-adjusted one-year outcomes, patients with S. maltophilia had a non-significant trend towards worse outcomes compared to patients without P. aeruginosa, but were more similar to patients with P aeruginosa., Discussion: Bronchiectasis patients with S. maltophilia may have worse outcomes than patients without this organism or without P. aeruginosa; further study is needed to determine if the non-significant trends we note are clinically significant., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: The aim of this study was to determine and compare the efficacy of drugs to treat Mycobacterium kansasii (Mkn) pulmonary disease by performing minimum inhibitory concentration (MIC) determination and time-kill studies., Methods: We determined the MICs to 13 drugs against the Mkn standard laboratory strain ATCC 12478 and 20 clinical isolates and performed time-kill studies with 18 drugs from different classes using the standard laboratory strain of Mkn. The β-lactam antibiotics were tested with or without the combination of the β-lactamase inhibitor avibactam. An inhibitory sigmoid E max model was used to describe the relationship between drug concentrations and bacterial burden., Results: Among the 13 tested drugs in the MIC experiments, the lowest MIC was recorded for bedaquiline. Among the 18 drugs used in the time-kill studies, maximum kill with cefdinir, tebipenem, clarithromycin, azithromycin, moxifloxacin, levofloxacin, tedizolid, bedaquiline, pretomanid and telacebac was greater than that for some of the drugs (isoniazid, rifampicin and ethambutol) used in standard combination therapy., Conclusion: We report preclinical data on the efficacy and potency of drugs that can potentially be repurposed to create a safe, effective and likely shorter-duration regimen for the treatment of Mkn pulmonary disease., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Bronchiectasis is a chronic lung condition frequently associated with nontuberculous mycobacteria pulmonary (NTM) disease. Persons with these conditions are at increased risk of mortality. Patient reported outcome (PRO) instruments and the 6-minute walk test (6MWT) have been shown to predict mortality for several lung conditions, but these measures have not been fully evaluated for bronchiectasis and NTM., Methods: We conducted a retrospective cohort study among adult patients enrolled in a natural history study of bronchiectasis at the National Heart, Lung, and Blood Institute. Electronic medical records were queried for demographic, clinical, microbiologic, radiographic, and PRO instrument data: St. George's Respiratory Questionnaire (SGRQ), Medical Research Council Dyspnea Scale, and the Pulmonary Symptom Severity Score (PSSS). The study baseline date was defined as the patient's first visit after January 1st, 2015 with a SGRQ or 6MWT completed. Follow-up was defined as the interval between the study baseline visit and date of death or December 31st, 2019. Sex-stratified Cox proportional-hazards regression was conducted to identify predictors of mortality. Separate models were run for each PRO and 6MWT measure, controlling for age, body mass index (BMI), fibrocavitary disease status, and M. abscessus infection., Results: In multivariable Cox proportional-hazards regression models, the PSSS-severity (aHR 1.29, 95% CI 1.04-1.59), the 6MWT total distance walked (aHR 0.938, 95% CI 0.896-0.981) and distance saturation product (aHR 0.930, 95% CI 0.887-0.974) independently predicted mortality. In addition, BMI was significantly predictive of mortality in all models., Conclusions: The 6MWT and a PRO instrument capturing symptom severity are independently predictive of mortality in our cohort of bronchiectasis patients., (© 2022. The Author(s).)

Immunodeficiency represents a vast number of diseases and syndromes. Both primary and secondary forms of immunodeficiency are important contributors to the development of bronchiectasis. Primary immune deficiencies, in particular, are increasingly identified and defined as contributors. Specific immune deficiencies that are closely associated with bronchiectasis and as discussed in this article are common variable immunodeficiency, specific antibody deficiency, immunodeficiencies involving immunoglobulin E, DOCK8 immunodeficiency, phosphoglucomutase 3 deficiency, activated phosphoinositide 3-kinase delta syndrome, and X-linked agammaglobulinemia. Each of these primary immune deficiencies has unique nuances. Vigilance for these unique signs and symptoms is likely to improve recognition of specific immunodeficiency in the idiopathic bronchiectasis patient. Secondary forms of immunodeficiency occur as a result of a separate disease process. Graft versus host disease, malignancy, and human immunodeficiency virus are three classic examples discussed in this article. An awareness of the potential for these disease settings to lead to bronchiectasis is necessary to optimize patient care. With understanding and mindfulness toward the intricate relationship between bronchiectasis and immunodeficiency, there is an opportunity to elucidate pathophysiologic underpinnings between these two syndromes., Competing Interests: None declared., (Thieme. All rights reserved.)

Rationale: Non-cystic fibrosis bronchiectasis (NCFB) is characterized by dilated bronchi, poor mucus clearance and susceptibility to bacterial infection. Pseudomonas aeruginosa (PA) is one of the most frequently isolated pathogens in patients with NCFB. The purpose of this study was to evaluate the association between presence of PA and disease severity in patients within the US Bronchiectasis and Nontuberculous mycobacteria (NTM) Research Registry (BRR)., Methods: Baseline US BRR data from adult patients with NCFB collected between 2008 and 2018 was used for this study. The presence of PA was defined as one or more positive PA cultures within two years prior to enrollment. Modified Bronchiectasis Severity Index (m-BSI) and modified FACED (m-FACED) were computed to evaluate severity of bronchiectasis. Unadjusted and multivariable multinomial regression models were used to assess the association between presence of PA and severity of bronchiectasis., Results: Average age of the study participants (n = 1831) was 63.7 years (SD = 14.1), 91.5% white, and 78.8% female. Presence of PA was identified in 25.4% of the patients. Patients with presence of PA had significantly lower mean pre-bronchodilator FEV1% predicted compared to those without PA (62.8% vs. 73.7%, p < .0001). In multivariate analyses, patients with presence of PA had significantly greater odds for having high (OR adj  = 6.15 (95%CI:3.98-9.50) and intermediate (OR adj  = 2.06 (95%CI:1.37-3.09) severity vs. low severity on m-BSI., Conclusion: The presence of PA is common in patients with NCFB within the Bronchiectasis and NTM Research Registry. Severity of bronchiectasis is significantly greater in patients with PA which emphasizes high burden of the disease., Competing Interests: Declaration of competing interest DA-H has served on a research protocol advisory board for AIT Therapeutics and has served in an educational lecture series sponsored by Insmed. TRA has participated in clinical trials sponsored by Bayer, Aradigm, Zambon, and Insmed but has not received any personal or research support. ABarker has received grant support from COPD Foundation for participation in the Bronchiectasis and NTM Research Registry. ABasavaraj has received grant support from COPD Foundation for participation in the Bronchiectasis and NTM Research Registry, has served on the advisory board and consultant for Insmed, and consultant for Hill-Rom. AS has served on the Speaker Bureau and Advisory Board for Insmed. CLD has received grant support from COPD Foundation and Insmed. DM is a former employee and a current shareholder of GlaxoSmithKline. MLAD has served on Speaker Bureau/Advisory Boards for Spark Partners and Insmed and participated in clinical trials for Zambon and Parion/Vertex. MLM has received grant support from COPD Foundation. PGN has received grant support from Aradigm/Grifols, Insmed, Parion/ Vertex and Bayer, and consultancy fees from Bayer, Grifols, and Smartvest. AEO has received grant support from Parion, Insmed, Aradigm, Grifols, and COPD Foundation. KNO has a Cooperative Research and Development Award with AIT Therapeutics (Beyond Air) and Matinas Biopharma and has participated on advisory panels with Insmed, Inc. MAS has received grant support from COPD Foundation, Parion, Bayer Healthcare, and Aradigm. BMT has received personal fees for serving on advisory boards for GlaxoSmithKline and AstraZeneca and helped cofound the COPD Foundation and served as the Foundation’s Board Chairman for ten years. GT has received grant support from the COPD Foundation for participation in the Bronchiectasis and NTM Research Registry and has received personal fees for serving on Advisory Boards for Bayer, Grifols, Aradigm, and Cipla. KLW has received grant support and personal fees from Insmed and Bayer. No conflicts declared from RC, AD, EE, KF, DG, MMJ, MRK and GS., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Increasing numbers of patients are being diagnosed with bronchiectasis, yet much remains to be elucidated about this heterogeneous patient population. We sought to determine the relationship between nutrition and health outcomes in non-cystic fibrosis (non-CF) bronchiectasis, using data from the U.S. Bronchiectasis Nontuberculous Mycobacterial Research Registry (U.S. BRR)., Methods: This was a retrospective, observational, longitudinal study using 5-year follow-up data from the BRR. Bronchiectasis was confirmed on computed tomography (CT). We stratified patients into nutrition categories using body mass index (BMI), and correlated BMI to markers of disease severity., Results: Overall, n = 496 patients (mean age 64.6- ± 13 years; 83.3% female) were included. At baseline 12.3% (n = 61) were underweight (BMI < 18.5kg/m 2 ), 63.9% (n = 317) had normal weight (BMI ≥ 18.5kg/m 2 and <25.0kg/m 2 ), 17.3% (n = 86) were overweight (BMI ≥ 25.0kg/m 2 and < 30.0kg/m 2 ), and 6.5% (n= 32) were obese (BMI ≥ 30kg/m 2 ). Men were overrepresented in the overweight and obese groups (25.6% and 43.8% respectively, p < 0.0001). Underweight patients had lower lung function (forced expiratory volume in 1 second [FEV 1 ] % predicted) than the other weight groups (64.5 ± 22, versus 73.5 ± 21, 68.5 ± 20, and 76.5 ± 21 in normal, overweight, and obese groups respectively, p = 0.02). No significant differences were noted between BMI groups for other markers of disease severity at baseline, including exacerbation frequency or hospitalization rates. No significant differences were noted in BMI distribution between patients with and without Pseudomonas , non-tuberculous mycobacteria, or by cause of bronchiectasis. The majority of patients demonstrated stable BMI over 5 years., Conclusions: Although underweight patients with bronchiectasis have lower lung function, lower BMI does not appear to relate to other markers of disease severity in this patient population., Competing Interests: Dr. Addrizzo-Harris reports consultant work from Insmed, advisory board work from AIT, outside the submitted work. Dr. Basavaraj reports grants from the COPD Foundation, personal fees from Hill-Rom, and personal fees from Insmed, outside the submitted work. Dr. Daley reports grants from the COPD Foundation, during the conduct of the study and grants from Insmed, outside the submitted work. Dr. Daniels reports grants and personal fees from Insmed, personal fees from Spark Healthcare, personal fees from International Biophysics Corporation, grants from Zambon, and grants from Parion/Vertex, outside the submitted work. Dr. Noone has received grant support from Aradigm/Grifols, Insmed, Parion/ Vertex and Bayer, and consultancy fees from Bayer, Grifols, and Smartvest. Dr. O'Donnell reports grants from the COPD Foundation/U.S. Bronchiectasis Research Registry, grants and personal fees from Insmed Inc, personal fees from Electromed and Merck, grants and personal fees from Bayer, personal fees from Xellia, and grants from Zambon, Aradigm, and Parion, outside the submitted work. Dr. Olivier reports grants from Beyond Air, Inc, and Matinas Biopharma, outside the submitted work. Dr. Philley reports personal fees from Insmed, Bayer, and Janssen, grants from REPORT trial, outside the submitted work. Dr. Tino reports grants from the U.S. BRR/COPD Foundation, advisory board work from Bayer, Grifols, Aradigm and Cipla, outside the submitted work. Dr. Salathe reports grants from the COPD Foundation (registry), during the conduct of the study; grants and personal fees from the National Institutes of Health, the Flight Attendant Medical Research Institute, and Arrowhead Pharmaceuticals and grants from the James and Esther King Florida Biomedical Research Program, outside the submitted work. Dr. Thomashow reports personal fees from GSK and Astra Zeneca, outside the submitted work. Dr. Winthrop reports grants and personal fees from Insmed, personal fees from Johnson and Johnson, Paratek, Red Hill Biopharma, and Horizon, outside the submitted work. Drs. Aksamit, Barker, Despotes, Choate, DiMango, Eden, Fennelly, Johnson, Knowles, McShane, Metersky, and Schmid have no conflicts of interest to disclose., (JCOPDF © 2020.)

Bronchiectasis is an important clinical syndrome because of its increasing prevalence, substantial economic burden on health care, and associated morbidity. Until recently, the disease was considered an orphan and essentially neglected from a therapeutic standpoint, but many recent advances have been made in the field. Several national registries have formed to provide databases from which to study patients with bronchiectasis. Experts published a consensus definition of a bronchiectasis-specific exacerbation that will serve as a unified definition for future clinical trials. Several inhaled antibiotic trials aimed at reducing exacerbation frequency have been completed. Researchers have investigated nonculture techniques, such as 16S ribosomal RNA (rRNA) and whole genome sequencing, to characterize the microbiological characteristics. Studies of anti-Pseudomonas antibodies are providing interesting insight into varying host responses to chronic Pseudomonas infection. After three successful trials demonstrating that macrolides reduce exacerbations in bronchiectasis, other antiinflammatory agents have been investigated, and a trial of a novel antiinflammatory drug is ongoing. A relatively robust study has been published in airway clearance, a therapy that is accepted universally as beneficial but that has never been accompanied by strong evidence. To build on the successes with bronchiectasis thus far, investigators must develop better definitions of phenotypes of bronchiectasis. In this regard, clinical tools have been developed to quantify disease severity and predict prognosis. Studies of different clinical phenotypes of bronchiectasis in patients with bronchiectasis have been published. With continued advances in the field of bronchiectasis, there is hope that evidenced-based therapies will become available., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Bronchiectasis refers to abnormal dilatation of the bronchi. Airway dilatation can lead to failure of mucus clearance and increased risk of infection. Pathophysiological mechanisms of bronchiectasis include persistent bacterial infections, dysregulated immune responses, impaired mucociliary clearance and airway obstruction. These mechanisms can interact and self-perpetuate, leading over time to impaired lung function. Patients commonly present with productive cough and recurrent chest infections, and the diagnosis of bronchiectasis is based on clinical symptoms and radiological findings. Bronchiectasis can be the result of several different underlying disorders, and identifying the aetiology is crucial to guide management. Treatment is directed at reducing the frequency of exacerbations, improving quality of life and preventing disease progression. Although no therapy is licensed for bronchiectasis by regulatory agencies, evidence supports the effectiveness of airway clearance techniques, antibiotics and mucolytic agents, such as inhaled isotonic or hypertonic saline, in some patients. Bronchiectasis is a disabling disease with an increasing prevalence and can affect individuals of any age. A major challenge is the application of emerging phenotyping and endotyping techniques to identify the patient populations who would most benefit from a specific treatment, with the goal of better targeting existing and emerging treatments and achieving better outcomes.

Bronchiectasis is a chronic respiratory disease with heterogeneous etiology, characterized by a cycle of bacterial infection and inflammation, resulting in increasing airway damage. Exacerbations are an important cause of morbidity and are strongly associated with disease progression. Many patients with bronchiectasis suffer from two or more exacerbations per year. However, there are no approved therapies to reduce or delay exacerbations in this patient population. Ciprofloxacin DPI is in development as a long-term, intermittent therapy to reduce exacerbations in patients with non-cystic fibrosis (CF) bronchiectasis and evidence of respiratory pathogens. Ciprofloxacin DPI combines drug substance, dry powder manufacturing technology, and an efficient, pocket-sized, dry powder inhaler to deliver an effective antibiotic directly to the site of infection, with minimal systemic exposure and treatment burden. Here we review the drug substance and particle engineering (PulmoSphere™) technology used, and key physical properties of Ciprofloxacin Inhalation Powder, including deposition, delivered dose uniformity, consistency, and stability. Design features of the T-326 Inhaler are described in relation to lung targeting, safety and tolerability of inhalation powders, as well as treatment burden and adherence. If approved, Ciprofloxacin DPI may provide a valuable treatment option for those with frequent exacerbations and respiratory pathogens., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Transmission electron microscopy (TEM) provides sub-nanometre-scale details in volumetric samples. Samples such as pathology tissue specimens are often stained with a metal element to enhance contrast, which makes them opaque to optical microscopes. As a result, it can be a lengthy procedure to find the region of interest inside a sample through sectioning. We describe micro-CT scouting for TEM that allows noninvasive identification of regions of interest within a block sample to guide the sectioning step. In a tissue pathology study, a bench-top micro-CT scanner with 10 μm resolution was used to determine the location of patches of the mucous membrane in osmium-stained human nasal scraping samples. Once the regions of interest were located, the sample block was sectioned to expose that location, followed by ultra-thin sectioning and TEM to inspect the internal structure of the cilia of the membrane epithelial cells with nanometre resolution. This method substantially reduced the time and labour of the search process from typically 20 sections for light microscopy to three sections with no added sample preparation., (© 2016 The Authors. Journal of Microscopy published by John Wiley & Sons Ltd on behalf of Royal Microscopical Society.)

Since pulmonary nontuberculous mycobacteria (PNTM) lung disease was last reviewed in CHEST in 2008, new information has emerged spanning multiple domains, including epidemiology, transmission and pathogenesis, clinical presentation, diagnosis, and treatment. The overall prevalence of PNTM is increasing, and in the United States, areas of highest prevalence are clustered in distinct geographic locations with common environmental and socioeconomic factors. Although the accepted paradigm for transmission continues to be inhalation from the environment, provocative reports suggest that person-to-person transmission may occur. A panoply of host factors have been investigated in an effort to elucidate why infection from this bacteria develops in ostensibly immunocompetent patients, and there has been clarification that immunocompetent patients exhibit different histopathology from immunocompromised patients with nontuberculous mycobacteria infection. It is now evident that Mycobacterium abscessus, an increasingly prevalent cause of PNTM lung disease, can be classified into three separate subspecies with differing genetic susceptibility or resistance to macrolides. Recent publications also raise the possibility of improved control of PNTM through enhanced adherence to current treatment guidelines as well as new approaches to treatment and even prevention. These and other recent developments and insights that may inform our approach to PNTM lung disease are reviewed and discussed.

There is renewed interest in non-cystic fibrosis bronchiectasis, which is a cause of significant morbidity in adults and can be diagnosed by high-resolution chest computed tomography scan. No longer mainly a complication after pulmonary infection with Mycobacterium tuberculosis, diverse disease processes and mechanisms have been demonstrated to result in the chronic cough, purulent sputum production, and airway dilation that characterize this disease. Improved understanding of the role of mucus stasis in causing bacterial colonization has led to increased emphasis on the use of therapies that enhance airway clearance. Inhalational antibiotics reduce the bacterial burden associated with a worse outcome. Low-dose, chronic macrolide therapy has been shown to decrease exacerbation frequency and airway inflammation. For the first time, a number of therapies for non-cystic fibrosis bronchiectasis are undergoing testing in clinical research trials designed specifically for this population. This concise clinical review focuses on the major etiologies, diagnostic testing, microbiology, and management of patients with adult non-cystic fibrosis bronchiectasis. Systematic evaluation identifies a specific cause in the majority of patients and may affect subsequent treatment. We outline current therapies and review the data that support their use.

The number of donors falls short of the number of patients on the wait list for lung transplantation making it necessary to ration the available donor organs. The ideal allocation system is guided by ethical principles and scientifically accurate at identifying patients who will gain the greatest degree of benefit from receiving the organ, in terms of both pre- and posttransplantation survival. The lung allocation score (LAS) was developed in 2005 to reduce mortality on the wait list, prioritize candidates based on urgency, minimize the role of geography, and maximize transplant benefit. The LAS has not made much of an impact on the geographic disparity of listing patients for lung transplantation, but it did achieve the goal of reducing wait-list mortality and prioritizing patients based on urgency. In prioritizing patients with the most urgent status, a new controversy has come into the forefront: whether or not the increased number of critically ill recipients maximizes transplant benefit. Despite the controversy, the LAS system is an improvement compared with the traditional first-come, first-served system, and it has even been adopted by Eurotransplant. In the future, as modifications are made to improve the LAS, the issue of critically ill patients and maximizing posttransplant benefit will be the focus., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Sirolimus (rapamycin) is a potent anti-proliferative agent with immunosuppressive properties that is increasingly being used in solid-organ and hematopoietic stem cell transplantation. In addition, this drug is being investigated for treatment of a broad range of disorders, including cardiovascular disease, malignancies, tuberous sclerosis, and lymphangeioleiomyomatosis. In this study, we found an increased risk of venous thromboembolism (VTE) in lung transplant recipients treated with a sirolimus (SIR)-based immunosuppressive regimen., Methods: One hundred eighty-one lung transplant recipients were enrolled in a prospective, multicenter, randomized, open-label trial comparing a tacrolimus (TAC)/SIR/prednisone immunosuppression regimen with a TAC/azathioprine (AZA)/prednisone immunosuppressive regimen. The differences in rates of VTE were examined., Results: There was a significantly higher occurrence of VTE in the SIR cohort [15 of 87 (17.2%)] compared with the AZA cohort [3 of 94 (3.2%)] (stratified log-rank statistic = 7.44, p < 0.01). When adjusted for pre-transplant diagnosis and stratified by transplant center, this difference remained essentially unchanged (hazard ratio for SIR vs AZA = 5.2, 95% confidence interval 1.4 to 19.5, p = 0.01)., Conclusion: Clinicians prescribing SIR should maintain a high level of vigilance for VTE, particularly among patients with other risk factors for this complication., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

This paper reviews efforts that have been made to minimize immunosuppression in lung transplant patients. A brief history of tolerance and its potential application to lung transplantation is also discussed.

Alveolar epithelial beta-adrenergic receptor (betaAR) activation accelerates active Na+ transport in lung epithelial cells in vitro and speeds alveolar edema resolution in human lung tissue and normal and injured animal lungs. Whether these receptors are essential for alveolar fluid clearance (AFC) or if other mechanisms are sufficient to regulate active transport is unknown. In this study, we report that mice with no beta1- or beta2-adrenergic receptors (beta1AR-/-/beta2AR-/-) have reduced distal lung Na,K-ATPase function and diminished basal and amiloride-sensitive AFC. Total lung water content in these animals was not different from wild-type controls, suggesting that betaAR signaling may not be required for alveolar fluid homeostasis in uninjured lungs. Comparison of isoproterenol-sensitive AFC in mice with beta1- but not beta2-adrenergic receptors to beta1AR-/-/beta2AR-/- mice indicates that the beta2AR mediates the bulk of beta-adrenergic-sensitive alveolar active Na+ transport. To test the necessity of betaAR signaling in acute lung injury, beta1AR-/-/beta2AR-/-, beta1AR+/+/beta2AR-/-, and beta1AR+/+/beta2AR+/+ mice were exposed to 100% oxygen for up to 204 hours. beta1AR-/-/beta2AR-/- and beta1AR+/+/beta2AR-/- mice had more lung water and worse survival from this form of acute lung injury than wild-type controls. Adenoviral-mediated rescue of beta2-adrenergic receptor (beta2AR) function into the alveolar epithelium of beta1AR-/-/beta2AR-/- and beta1AR+/+/beta2AR-/- mice normalized distal lung beta2AR function, alveolar epithelial active Na+ transport, and survival from hyperoxia. These findings indicate that betaAR signaling may not be necessary for basal AFC, and that beta2AR is essential for the adaptive physiological response needed to clear excess fluid from the alveolar airspace of normal and injured lungs.