Recombinant Alpha-1 Antitrypsin-Fc Fusion Protein INBRX-101 in Adults With Alpha-1 Antitrypsin Deficiency: A Phase 1 Study.

Background: Alpha-1 antitrypsin deficiency (AATD) is characterized by low alpha-1 antitrypsin (AAT) levels, predisposing individuals to lung disease. The standard of care, plasma-derived AAT (pdAAT), is delivered as weekly infusions to maintain serum AAT concentrations ≥11µM (≈50% of those in healthy individuals). INBRX-101, a recombinant human AAT-Fc fusion protein, was designed to have a longer half-life and achieve higher AAT levels than pdAAT. Methods: In this phase 1 dose-escalation study (N=31), adults with AATD received 1 dose (part 1) or 3 doses (part 2) of 10 (part 1), 40, 80, or 120mg/kg INBRX-101 every 3 weeks (Q3W) via intravenous infusion. The primary endpoint was safety and tolerability. Secondary endpoints were pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of INBRX-101. Results: INBRX-101 was well tolerated. Most treatment-emergent adverse events were grade ≤2. In part 2 (n=18; each dose, n=6), dose-related increases in serum functional AAT (fAAT) were observed; mean fAAT levels remained above the 21 µM target for up to 4 weeks after the final dose in the 120-mg/kg cohort. Antidrug antibodies had no meaningful impact on PK or PD. INBRX-101 was detected in pulmonary epithelial lining fluid (PELF) from all patients assessed (n=11), and PELF fAAT increased after dosing. PK/PD modeling projected steady-state serum fAAT ≥21µM at 120 mg/kg Q3W (average concentration ≈43µM; trough concentration ≈28µM) and Q4W (≈34µM; ≈21µM). Conclusion: The favorable safety profile and ability to maintain serum fAAT levels >21µM with extended-interval dosing, support a phase 2 trial evaluating Q3W and Q4W dosing of INBRX-101.

Development of a risk score to increase detection of severe alpha-1 antitrypsin deficiency.

Background: Alpha-1 antitrypsin deficiency (AATD) is an under-recognised genetic cause of chronic obstructive lung disease, and many fewer cases than estimated have been identified. Can a reported respiratory and hepatic disease history from a large AATD testing database be used to stratify a person's risk of severe AATD? Methods: We analysed data extracted from the AATD National Detection Program. Demographics and medical history were evaluated to predict AATD PI*ZZ genotype. Logistic regression and integer programming models identified predictors and obtained risk scores. These were internally validated on a subset of the data. Results: Out of 301 343 subjects, 1529 (0.5%) had PI*ZZ genotype. Predictors of severe AATD were asthma, bronchitis, emphysema, allergies, bronchiectasis, family history of AATD, cirrhosis, hepatitis and history of abnormal liver function tests. The derived model establishes a subject's risk of severe AATD, and scores ≥0 had an estimated risk of 0.41%, sensitivity 84.62% and specificity 24.32%. A model simulating guideline recommendations had an estimated risk of 0.51% with a sensitivity of 37.98% and specificity 46.60%. By recommending screening for scores ≥0, we estimate that more subjects would be screened (75.7% versus 53.4%) and detected (84.6% versus 58.2%) compared to a guideline-simulated model. Conclusion: This medical history risk model is a useful predictive tool to detect subjects at greater risk of having severe AATD and improves sensitivity of detection. Scores <0 are at lower risk and may need not be screened; testing is recommended for scores ≥0 and consistent with current guidelines.

Testing Patterns and Disparities for Alpha-1 Antitrypsin Deficiency.

BACKGROUND: Alpha-1 antitrypsin deficiency is an under-recognized genetic cause of chronic lung and liver disease; it remains unclear what the testing frequency and disparities are for alpha-1 antitrypsin deficiency. METHODS: This is a retrospective cohort study of people with newly diagnosed chronic obstructive pulmonary disease and liver disease identified at the University of Florida between January 1, 2012 and December 31, 2021. We performed incidence and prevalence analysis for alpha-1 antitrypsin (AAT) testing and point-biserial correlation analysis for tobacco use and AAT testing. We evaluated characteristics with AAT testing using adjusted multivariable logistic regression. RESULTS: Among 75,810 subjects with newly diagnosed chronic obstructive pulmonary disease and liver disease between 2012 and 2021, 4248 (5.6%) were tested for AAT deficiency. All subjects had an AAT level performed, while 1654 (39%) had phenotype testing. Annual incidence of testing increased for subjects with newly diagnosed chronic obstructive pulmonary disease or liver disease from 2.8% and 5.4%, respectively, in 2012 to 4.1% and 11.3%, respectively, in 2021. Adjusted multivariable regression analysis showed factors favoring AAT testing were White race, and concomitant chronic obstructive pulmonary disease and liver disease. Increasing age, non-White race, current tobacco use, and being a male with chronic obstructive pulmonary disease had lower odds of AAT testing. CONCLUSION: Although slowly improving, testing for AAT deficiency continues to have a low uptake in the clinical setting despite guidelines recommending broader testing. Individuals of White race and those with concomitant chronic obstructive pulmonary disease and liver disease are more likely to be tested, while older subjects, individuals of non-White race, current tobacco use, and men with chronic obstructive pulmonary disease are less favored to be tested.

Lung microhaemorrhage drives oxidative/inflammatory damage in α1-antitrypsin deficiency.

Background: Animal models using intratracheal instillation show that elastase, unopposed by α1-antitrypsin (AAT), causes alveolar damage and haemorrhage associated with emphysematous changes. The aim of the present study was to characterise any relationship between alveolar haemorrhage and human AAT deficiency (AATD) using bronchoalveolar lavage (BAL) and lung explant samples from AATD subjects. Methods: BAL samples (17 patients, 15 controls) were evaluated for free haem (iron protoporphyrin IX) and total iron concentrations. Alveolar macrophage activation patterns were assessed using RNA sequencing and validated in vitro using haem-stimulated, monocyte-derived macrophages. Lung explants (seven patients, four controls) were assessed for iron sequestration protein expression patterns using Prussian blue stain and ferritin immunohistochemistry, as well as ferritin iron imaging and elemental analysis by transmission electron microscopy. Tissue oxidative damage was assessed using 8-hydroxy-2'-deoxyguanosine immunohistochemistry. Results: BAL collected from AATD patients showed significantly elevated free haem and total iron concentrations. Alveolar and interstitial macrophages in AATD explants showed elevated iron and ferritin accumulation in large lysosomes packed by iron oxide cores with degraded ferritin protein cages. BAL macrophage RNA sequencing showed innate pro-inflammatory activation, replicated in vitro by haemin exposure, which also triggered reactive oxygen species generation. AATD explants showed massive oxidative DNA damage in both lung epithelial cells and macrophages. Conclusions: BAL and tissue markers of alveolar haemorrhage, together with molecular and cellular evidence of macrophage innate pro-inflammatory activation and oxidative damage, are consistent with free haem stimulation. Overall, this initial study provides evidence for a pathogenetic role of elastase-induced alveolar haemorrhage in AATD emphysema.

Therapeutic drug monitoring in cystic fibrosis and associations with pulmonary exacerbations and lung function.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy have resulted in longer life expectancies, yet pulmonary exacerbations remain a leading cause of morbidity. Intravenous antibiotics is the mainstay treatment, however achieving adequate concentrations remains challenging. The effect of therapeutic drug monitoring (TDM) of beta-lactams on exacerbations and lung function has not been studied. METHODS: Patient demographics, antibiotic regimens, forced expiratory volume 1 s (FEV1), and exacerbation history was obtained from 32 patients with cystic fibrosis admitted for exacerbations. All patients were colonized with Pseudomonas aeruginosa, received CFTR therapy for at least one year, and had 3-month interval follow ups. Plasma concentrations, FEV1, and exacerbation history was obtained before and after therapeutic drug monitoring. This included peak and trough plasma concentrations of piperacillin-tazobactam and cefepime using liquid chromatography with mass spectrometry. T-test and Mann-Whitney U test were used to compare medians/means of FEV1 and pulmonary exacerbations pre and post-TDM as well as free trough-to-minimum inhibitory concentration ratio (fCmin/MIC) ≥1 and ≥ 4. RESULTS: TDM was associated with decreased exacerbations/year from 1.91 to 1.31 (p = 0.04) and among the cohort with >/ = 2 exacerbations per year, there was a longer exacerbation free interval after TDM (196.2 vs 103.7 days, p = 0.02). The decline in FEV1% predicted after therapeutic drug monitoring to the first exacerbation was -4.9 compared to -9.7 prior (p = 0.03). CONCLUSIONS: TDM for cystic fibrosis pulmonary exacerbations results in decreased pulmonary exacerbations, longer intervals to pulmonary exacerbation, and lower decline in FEV1% predicted.

Impact of a Computerized Clinical Decision Support System to Improve Chronic Obstructive Pulmonary Disease Diagnosis and Testing for Alpha-1 Antitrypsin Deficiency.

Rationale: Chronic obstructive pulmonary disease (COPD) and alpha-1 antitrypsin deficiency (AATD) are underrecognized diseases. This is in part due to the underdiagnosis and lack of confirmation of COPD but also from poor adherence to AATD screening recommendations. Objectives: A clinical decision support system (CDSS) to guide primary care providers improves spirometry testing and confirmation of COPD diagnosis in subjects at risk and improves AATD screening in patients with confirmed COPD. Methods: A CDSS was created to be applied to all Veterans attending single-center Veterans Affairs primary care clinics. The CDSS had an algorithmic dialogue with components executed in phases during different clinic visits: screening for COPD risk using the COPD population screening (COPD-PS) questionnaire, spirometry recommendation, and ordering tool for subjects with a prior diagnosis of COPD or subjects considered high risk by the COPD-PS, dialogue to confirm or discard the diagnosis of COPD, and recommendations for AATD screening in subjects with confirmed COPD. The latter was performed by ordering alpha-1 antitrypsin (AAT) serum levels. Each step of the CDSS algorithm approach was recorded and available to be retrieved at a later date for analysis. Results: Over 6 years, a total of 6,235 Veterans >40 years of age completed the CDSS. According to the COPD-PS questionnaire, 962 (18.5%) subjects were identified as high risk for COPD. An additional 579 subjects with a prior diagnosis of COPD also entered the subsequent steps of the CDSS algorithm. Of the high-risk cohort, the CDSS led to an increase in spirometry testing from 24% to 83% and led to a new diagnosis of COPD in 342 (43%). In the prior COPD diagnosis group, spirometry testing increased from 58% to 84%, leading to COPD reconfirmation in only 326 (67%). A total of 489 (68%) subjects with confirmed COPD completed AAT testing prompted by the CDSS, with 23 subjects identified with AATD and one with severe AATD. Conclusions: In the Veterans Affairs system, the use of a clinical decision support system algorithm that incorporates screening for COPD and AATD improves COPD over- and underdiagnosis and screening rates of AATD in a primary care setting.

Lung Inflammation in alpha-1-antitrypsin deficient individuals with normal lung function.

BACKGROUND: Alpha-1-antitrypsin deficient (AATD) individuals are prone to develop early age of onset chronic obstructive pulmonary disease (COPD) more severe than non-genetic COPD. Here, we investigated the characteristics of lower respiratory tract of AATD individuals prior to the onset of clinically significant COPD. METHODS: Bronchoalveolar lavage was performed on 22 AATD with normal lung function and 14 healthy individuals. Cell counts and concentrations of proteases, alpha-1-antitrypsin and proinflammatory mediators were determined in the bronchoalveolar lavage fluid from study subjects. In order to determine the airway inflammation, we also analyzed immune cell components of the large airways from bronchial biopsies using immunohistochemistry in both study subjects. Finally, we made comparisons between airway inflammation and lung function rate of decline using four repeated lung function tests over one year in AATD individuals. RESULTS: AATD individuals with normal lung function had 3 folds higher neutrophil counts, 2 folds increase in the proteases levels, and 2-4 folds higher levels of IL-8, IL-6, IL-1ß, and leukotriene B4 in their epithelial lining fluid compared to controls. Neutrophil elastase levels showed a positive correlation with the levels of IL-8 and neutrophils in AATD epithelial lining fluid. AATD individuals also showed a negative correlation of baseline FEV1 with neutrophil count, neutrophil elastase, and cytokine levels in epithelial lining fluid (p < 0.05). In addition, we observed twofold increase in the number of lymphocytes, macrophages, neutrophils, and mast cells of AATD epithelial lining fluid as compared to controls. CONCLUSION: Mild inflammation is present in the lower respiratory tract and airways of AATD individuals despite having normal lung function. A declining trend was also noticed in the lung function of AATD individuals which was correlated with pro-inflammatory phenotype of their lower respiratory tract. This results suggest the presence of proinflammatory phenotype in AATD lungs. Therefore, early anti-inflammatory therapies may be a potential strategy to prevent progression of lung disease in AATD individuals.

Evaluation of Clinical Predictors for Major Outcomes in Patients Hospitalized With COVID-19: The Potential Role of the Rothman Index.

Introduction The Rothman Index (RI, PeraHealth, Inc. Charlotte, NC, USA) is a predictive model intended to provide continuous monitoring of a patient's clinical status. There is limited data to support its use in the risk stratification of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We hypothesized that low admission RI scores would correlate with higher rates of adverse outcomes in patients hospitalized for coronavirus disease 2019 (COVID-19). Methods Medical records of adult patients admitted to a single 1,200-bed tertiary academic center were retrospectively reviewed for demographic data, baseline characteristics, RI scores, admission to intensive care unit (ICU), need for mechanical ventilation, and inpatient mortality. Statistical analyses were performed using STATA statistical software, version 17 (Stata Corp LLC, College Station, TX, USA). Continuous variables were analyzed using the Mann-Whitney test, and categorical variables were analyzed using Fisher's exact test. Both univariate and multivariate analyses were performed. A p-value <0.05 was considered statistically significant. Results Median admission RI score for the entire cohort was 63.0 (IQR 45.0 - 77.1). The cohort was divided by admission RI into a low-risk group (RI ≥70; n=70) and a high-risk group (RI <70; n=107). Compared to patients with low-risk RI, patients with high-risk RI had higher mortality (95.2%, 95% CI: 85.8 - 105 vs 4.8%, 95% CI: -5 - 14.2, p < 0.01), were more likely to require ICU admission (90.2%, 95% CI: 81.9 - 98.5 vs 9.8%, 95% CI: 1.5 - 18.1, p < 0.01) and mechanical ventilation (89.7%, 95% CI: 78.3 - 101 vs 10.3%, 95% CI: -1 - 21.7, p < 0.01), and had a longer median hospital length of stay (12 days, 95% CI: 9 - 14 vs 5 days, 95% CI: 4 - 7, p < 0.01). Conclusions High-risk RI was associated with increased admission to the ICU, mechanical ventilation, and mortality. These results suggest that it may be used as a tool to aid provider judgment in the setting of COVID-19.

Correlation of alpha-1 antitrypsin levels and exosome associated neutrophil elastase endothelial injury in subjects with SARS-CoV2 infection.

BACKGROUND: Severe acute respiratory syndrome caused by a novel coronavirus 2 (SARS-CoV-2) has infected more than 18 million people worldwide. The activation of endothelial cells is a hallmark of signs of SARS-CoV-2 infection that includes altered integrity of vessel barrier and endothelial inflammation. OBJECTIVES: Pulmonary endothelial activation is suggested to be related to the profound neutrophil elastase (NE) activity, which is necessary for sterilization of phagocytosed bacterial pathogens. However, unopposed activity of NE increases alveolocapillary permeability and extracellular matrix degradation. The uncontrolled protease activity of NE during the inflammatory phase of lung diseases might be due to the resistance of exosome associated NE to inhibition by alpha-1 antitrypsin. METHOD: 31 subjects with a diagnosis of SARS-CoV2 infection were recruited in the disease group and samples from 30 voluntaries matched for age and sex were also collected for control. RESULTS: We measured the plasma levels of exosome-associated NE in SARS-CoV-2 patients which, were positively correlated with sign of endothelial damage in those patients as determined by plasma levels of LDH. Notably, we also found strong correlation with plasma levels of alpha-1 antitrypsin and exosome-associated NE in SARS-CoV-2 patients. Using macrovascular endothelial cells, we also observed that purified NE activity is inhibited by purified alpha-1 antitrypsin while, NE associated with exosomes are resistant to inhibition and show less sensitivity to alpha-1 antitrypsin inhibitory activity, in vitro. CONCLUSIONS: Our results point out the role of exosome-associated NE in exacerbation of endothelial injury in SARS-CoV-2 infection. We have demonstrated that exosome-associated NE could be served as a new potential therapeutic target of severe systemic manifestations of SARS-CoV-2 infection.

Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder most commonly secondary to a single mutation in the SERPINA1 gene (PI*Z) that causes misfolding and accumulation of alpha-1 antitrypsin (AAT) in hepatocytes and mononuclear phagocytes which reduces plasma AAT and creates a toxic gain of function. This toxic gain of function promotes a pro-inflammatory phenotype in macrophages that contributes to lung inflammation and early-onset COPD, especially in individuals who smoke cigarettes. The aim of this study is to determine the role of cigarette exposed AATD macrophages and bronchial epithelial cells in AATD-mediated lung inflammation. METHODS: Peripheral blood mononuclear cells from AATD and healthy individuals were differentiated into alveolar-like macrophages and exposed to air or cigarette smoke while in culture. Macrophage endoplasmic reticulum stress was quantified and secreted cytokines were measured using qPCR and cytokine ELISAs. To determine whether there is "cross talk" between epithelial cells and macrophages, macrophages were exposed to extracellular vesicles released by airway epithelial cells exposed to cigarette smoke and their inflammatory response was determined. RESULTS: AATD macrophages spontaneously produce several-fold more pro-inflammatory cytokines as compared to normal macrophages. AATD macrophages have an enhanced inflammatory response when exposed to cigarette smoke-induced extracellular vesicles (EVs) released from airway epithelial cells. Cigarette smoke-induced EVs induce expression of GM-CSF and IL-8 in AATD macrophages but have no effect on normal macrophages. Release of AAT polymers, potent neutrophil chemo attractants, were also increased from AATD macrophages after exposure to cigarette smoke-induced EVs. CONCLUSIONS: The expression of mutated AAT confers an inflammatory phenotype in AATD macrophages which disposes them to an exaggerated inflammatory response to cigarette smoke-induced EVs, and thus could contribute to progressive lung inflammation and damage in AATD individuals.

Exploring the effects of social capital on the compulsive use of online social networks in civil unrest contexts.

The use of online social networking sites has become part of everyday life for more than three billion people worldwide. However, its use may go beyond being a habit, leading to compulsive use behaviours that jeopardize the well-being of an individual and the whole society. This study proposes and evaluates a theoretical model that examines the four dimensions of social capital, mediated by bonding and bridging social capital, as drivers of compulsive use of online social networks in the context of civil unrest. We evaluate the model using partial least squares structural equation modelling with data collected from a developing country. We found that reciprocity is the most important driver for bonding and bridging social capital with online members. Whereas trust, contradicting most of the literature in the field, was not statistically significant over bonding and bridging social capital. Bonding social capital shows a significant association with compulsive use behaviour. On the other hand, the effect of bridging social capital on compulsive use behaviour, although not significant, may become significant in the presence of a strong usage habit.

Outcomes and survival following lung transplantation in non-cystic fibrosis bronchiectasis.

Disease-specific outcomes in patients with non-cystic fibrosis bronchiectasis following lung transplantation are not well described. We performed a retrospective analysis to describe outcomes in these patients. Patients with non-cystic fibrosis bronchiectasis who have undergone lung transplantation in the USA were identified using the Organ Procurement and Transplant Network database. Survival data were analysed for the post-lung allocation score period with Kaplan-Meier curves, and a log-rank test was conducted to compare survival data among an age-, sex- and activation date-matched non-cystic fibrosis bronchiectasis cohort. 721 patients with non-cystic fibrosis bronchiectasis were listed for lung transplantation between March 1992 and September 2019. 407 patients received lung transplantation with a median age at listing of 47 years. The Kaplan-Meier survival analysis for lung transplantation recipient non-cystic fibrosis bronchiectasis patients during the post-lung allocation score period at 1, 5 and 10 years was 87%, 53% and 16%, respectively. The median survival time post-lung transplantation is 6.0 years (interquartile range: 2.3-11.9 years), which is similar to an age- and sex-matched cohort (p=0.86). This retrospective analysis demonstrates that median survival after lung transplantation in non-cystic fibrosis bronchiectasis was similar to other lung transplantation recipients over the study period. We suggest that the development of specific criteria for lung transplantation in non-cystic fibrosis bronchiectasis may improve patient selection and benefit a larger group of patients with this therapy.

Labelling Alpha-1 antitrypsin deficiency in the medical record - A call to action.

Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant genetic cause of chronic obstructive pulmonary disease (COPD) with over 100 allelic variants described. The normal allele is termed "M"; whereas, the "Z" and "S" alleles are the most common abnormal alleles. The ZZ combination accounts for 95% of cases with severe disease. We described the characteristics of patients given the label of AATD in the medical record. Our analysis found there is significant heterogeneity with regards to labelling subjects with AATD in the medical record, and this was true irrespective of the subjects age, gender, PFT measurements, tobacco pack years, or if the physician was a pulmonologist. In summary, this study highlights the need for continued investigation of the role of other mutations developing disease and options for more specific labelling of subjects with non-severe AATD and severe AATD to provide additional clarity for the patient and healthcare providers.

Testing the effects of combining azithromycin with inhaled tobramycin for P. aeruginosa in cystic fibrosis: a randomised, controlled clinical trial.

RATIONALE: Inhaled tobramycin and oral azithromycin are common chronic therapies in people with cystic fibrosis and Pseudomonas aeruginosa airway infection. Some studies have shown that azithromycin can reduce the ability of tobramycin to kill P. aeruginosa. This trial was done to test the effects of combining azithromycin with inhaled tobramycin on clinical and microbiological outcomes in people already using inhaled tobramycin. We theorised that those randomised to placebo (no azithromycin) would have greater improvement in forced expiratory volume in one second (FEV1) and greater reduction in P. aeruginosa sputum in response to tobramycin. METHODS: A 6-week prospective, randomised, placebo-controlled, double-blind trial testing oral azithromycin versus placebo combined with clinically prescribed inhaled tobramycin in individuals with cystic fibrosis and P. aeruginosa airway infection. RESULTS: Over a 6-week period, including 4 weeks of inhaled tobramycin, the relative change in FEV1 did not statistically significantly differ between groups (azithromycin (n=56) minus placebo (n=52) difference: 3.44%; 95% CI: -0.48 to 7.35; p=0.085). Differences in secondary clinical outcomes, including patient-reported symptom scores, weight and need for additional antibiotics, did not significantly differ. Among the 29 azithromycin and 35 placebo participants providing paired sputum samples, the 6-week change in P. aeruginosa density differed in favour of the placebo group (difference: 0.75 log10 CFU/mL; 95% CI: 0.03 to 1.47; p=0.043). CONCLUSIONS: Despite having greater reduction in P. aeruginosa density in participants able to provide sputum samples, participants randomised to placebo with inhaled tobramycin did not experience significantly greater improvements in lung function or other clinical outcomes compared with those randomised to azithromycin with tobramycin.

CFTR modulator use in post lung transplant recipients.

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator therapy has previously been contraindicated in solid organ transplant recipients. This was due to lack of data and concern for interactions with immunosuppressive drug regimens. However, in post-lung transplant recipients, CFTR modulators may improve extrapulmonary manifestations of cystic fibrosis without impacting graft function or immunosuppressive drug levels. Herein, we present our single center experience with the use of elexacaftor/tezacaftor/ivacaftor, Trikafta, in adult post-lung transplant recipients.

Gender and racial disparities in lung transplantation in the United States.

BACKGROUND: Lung transplant (LT) allocation utilizes a scoring system to prioritize patients, although data evaluating the access by gender and race remains limited. The study objective was to determine whether gender and racial disparities exist in patients listed for LT. METHODS: This was a retrospective analysis using the Organ Procurement and Transplant Network database of patients listed for a LT from 1984 until 2019. Nominal multivariate logistic regression analysis was performed to evaluate LT allocation by gender, race, and primary lung disease. Kaplan-Meier curves were constructed to compare rates of mortality over time. RESULTS: Sixty thousand eight hundred and forty-seven patients were listed between February 1984 and September 2019. Males comprised the majority of listed and transplanted patients at 51.7% and 55.8% respectively. In the LAS era, the median waiting list time for transplanted males was 43 days (interquartile range [IQR] 13-126), and females waited a median of 80 days (IQR 24-233) (p < .001). Persons of White race accounted for 82.6% and 84.3% of listed and transplanted patients respectively. Logistic regression analysis found that in the LAS era, males had an increased odds for LT allocation (OR 1.19, CI 1.12-1.27, p < .001) compared to females, and persons of White race (OR 1.23, CI 1.16-1.32, p < .001) compared to all other races combined. CONCLUSIONS: The majority of listed and transplanted patients in the United States were males and persons of White race. Also, being a male or person of White race had an outcome favoring lung transplant allocation compared to an appropriately matched person of another gender or race.

Association of Systemic Endothelial-Derived and Platelet-Derived Microparticles With Clinical Outcomes in Chronic Obstructive Pulmonary Disease.

PURPOSE: Endothelial and platelet microparticles (eMPs and pMPs), markers of cellular activation, dysfunction, or apoptosis, have been associated with multiple cardiovascular conditions. Chronic obstructive pulmonary disease (COPD) is associated with cardiovascular comorbidities and platelet/endothelial dysfunction. We analyzed whether eMPs and pMPs are associated with COPD status and/or severity. PATIENTS AND METHODS: A total of 58 COPD patients and 19 controls were enrolled and followed for an average of 1.17 years. Characterization of COPD included lung function, Body mass index-airflow Obstruction-Dyspnea-Exercise (BODE) scores, health-related quality of life, exacerbations, comorbidities, and mortality. Plasma collection to measure eMPs and pMPs via flow cytometry was performed at enrollment as well as during acute exacerbation in 17 participants. We measured pMPs (CD31+, CD41+31+, CD 62P+), eMPs (ULEX lectin+, CD51+, CD54+, CD62E+), the apoptotic CD62E+/CD31+ ratio, and Annexin V MP. RESULTS: As a group, COPD participants had no difference in all MP levels studied compared with controls. No significant correlations with diffusion capacity for carbon monoxide, quality of life, and exacerbation status were found in all MPs studied. However, the eMP ULEX and the pMP CD 62P+ were higher among COPD Global initiative for chronic Obstructive Lung Disease (GOLD) stage 3 patients compared to controls. The CD62E+/CD31+ ratio was lower in controls and GOLD stage 1 COPD participants compared with GOLD stage 2/3 COPD participants, suggesting increased apoptosis. eMP ULEX lectin+ decreased during acute exacerbations and pMP41+31+ significantly increased as BODE score increased. CONCLUSIONS: After adjusting for comorbidities, most eMPs and pMPs studied do not correlate significantly with COPD status or severity.

Oral cysteamine as an adjunct treatment in cystic fibrosis pulmonary exacerbations: An exploratory randomized clinical trial.

BACKGROUND: Emerging data suggests a possible role for cysteamine as an adjunct treatment for pulmonary exacerbations of cystic fibrosis (CF) that continue to be a major clinical challenge. There are no studies investigating the use of cysteamine in pulmonary exacerbations of CF. This exploratory randomized clinical trial was conducted to answer the question: In future pivotal trials of cysteamine as an adjunct treatment in pulmonary exacerbations of CF, which candidate cysteamine dosing regimens should be tested and which are the most appropriate, clinically meaningful outcome measures to employ as endpoints? METHODS AND FINDINGS: Multicentre double-blind randomized clinical trial. Adults experiencing a pulmonary exacerbation of CF being treated with standard care that included aminoglycoside therapy were randomized equally to a concomitant 14-day course of placebo, or one of 5 dosing regimens of cysteamine. Outcomes were recorded on days 0, 7, 14 and 21 and included sputum bacterial load and the patient reported outcome measures (PROMs): Chronic Respiratory Infection Symptom Score (CRISS), the Cystic Fibrosis Questionnaire-Revised (CFQ-R); FEV1, blood leukocyte count, and inflammatory markers. Eighty nine participants in fifteen US and EU centres were randomized, 78 completed the 14-day treatment period. Cysteamine had no significant effect on sputum bacterial load, however technical difficulties limited interpretation. The most consistent findings were for cysteamine 450mg twice daily that had effects additional to that observed with placebo, with improved symptoms, CRISS additional 9.85 points (95% CI 0.02, 19.7) p = 0.05, reduced blood leukocyte count by 2.46x109 /l (95% CI 0.11, 4.80), p = 0.041 and reduced CRP by geometric mean 2.57 nmol/l (95% CI 0.15, 0.99), p = 0.049. CONCLUSION: In this exploratory study cysteamine appeared to be safe and well-tolerated. Future pivotal trials investigating the utility of cysteamine in pulmonary exacerbations of CF need to include the cysteamine 450mg doses and CRISS and blood leukocyte count as outcome measures. CLINICAL TRIAL REGISTRATION: NCT03000348; www.clinicaltrials.gov.