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Franck F Rahaghi,1 Richard Monk,2 Viswanathan Ramakrishnan,3 Tatsiana Beiko,2 Charlie Strange2 1Department of Pulmonary and Critical Care, Cleveland Clinic Florida, Weston, FL, USA; 2Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA; 3Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USACorrespondence: Franck F RahaghiDepartment of Pulmonary and Critical Care, Cleveland Clinic Florida, Weston, FL, USATel +1 954 659 5450Fax +1 954 6595451Email rahaghf@ccf.orgPurpose: The extent of the survival benefit of augmentation therapy for alpha-1 antitrypsin deficiency (AATD) in individuals with advanced COPD is difficult to define. We performed a retrospective analysis using all available data from the observational registry of individuals with severe deficiency of alpha-1 antitrypsin (AAT) conducted by the NHLBI investigators.Patients and Methods: Individuals (N=1129) with severe deficiency of AAT were evaluated for mortality using all data sources and stratified by 10% increments of baseline forced expiratory volume in 1 second (FEV1) percent predicted and by augmentation therapy status (ever receiving versus never receiving). Kaplan–Meier survival curves were constructed for each of the deciles comparing survival in treated vs non-treated groups. A multivariable model was performed to define the correlates of survival in individuals with FEV1 < 30% predicted.Results: Amongst all subjects, augmentation was associated with improved survival (p< 0.0001). Among the individuals ever receiving augmentation therapy, survival was better than for those not receiving augmentation at all 10% increments of FEV1% predicted from 10% to 60% (P values < 0.05 in all deciles). In subgroups of participants with hyperinflation defined as residual volume (RV)> 120% predicted and in subgroups of participants with reduced diffusing capacity for carbon monoxide (DLCO) < 70% predicted, there was significantly better survival for those ever receiving augmentation therapy than for those who never received augmentation (p< 0.001). A multivariable analysis showed that mortality benefit is influenced by age, DLCO % predicted, and augmentation therapy.Conclusion: There is a survival benefit from augmentation therapy in AATD between FEV1 values in the 10– 60% predicted range. Screening and treatment of AATD patients should therefore not be limited by the severity of illness as defined by FEV1.Keywords: alpha-1 antitrypsin deficiency, COPD, mortality, augmentation therapy, FEV1, survival

Tatsiana Beiko, Charlie StrangeDivision of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC, USAAbstract: Chronic physical illness is associated with significant vulnerability for emotional disorders. Some studies suggest anxiety and depression are common comorbidities in individuals with alpha-1 antitrypsin deficiency (AATD). Many aspects of AATD contribute to quality of life impairment. Delays in diagnosis, high costs of disease treatment, and inherited genetic risk add to the symptom burden of lung or liver disease to alter quality of life. Whether anxiety and depression independently contribute to quality of life impairment remains unproven. In this article, we aim to review current literature examining the impact of anxiety and depression on the quality of life of AATD-affected individuals. Multifaceted approaches may best meet the needs of a heterogeneous population and are the best future strategies to minimize these emotional impacts and assure highest quality of life possible. More research studies are needed to achieve this ambitious goal and make life of AATD-affected individuals better by minimizing the effects of anxiety and depression.Keywords: anxiety, depression, alpha-1 antitrypsin deficiency

Background: The Step Forward Study (SFS) was designed to increase exercise activity and improve body mass index (BMI) among individuals with alpha-1 antitrypsin deficiency (AATD)-associated lung disease., Methods: The SFS is a randomized trial of an intensive distance intervention that was delivered via a series of mailings and teleconferences versus no additional intervention. All participants (n=500) were also enrolled in a disease management program designed for individuals with AATD-associated lung disease who have been prescribed augmentation therapy. The primary outcome was self-reported number of exercise minutes per week. The secondary outcome was BMI. Linear mixed model analyses were used to assess the difference in average weekly exercise minutes between the intervention arms over time. T-tests, signed rank and Wilcoxon rank-sum tests were used to evaluate changes in BMI between the intervention arms and within each BMI category., Results: The study included 429 individuals with evaluable primary outcome data.There was a significant effect of intervention on exercise minutes over time (p =0.018). Participants in the intervention group reported an average of 167.14 minutes (standard deviation [SD]=10.68) of weekly exercise and those in the standard care group reported 148.31 minutes (SD=10.96). There was a significant difference in BMI change between the intervention (mean BMI decrease 0.74, SD=2.16) and the standard care group (mean BMI decrease 0.27, SD=1.63); p =0.0122., Conclusion: Individuals who were randomly assigned to the intervention group reported more exercise activity and improvements in BMI over the course of this multicomponent intervention compared to individuals assigned to standard care., Competing Interests: DMM is a former employee and current shareholder of GlaxoSmithKline. RAS has served on advisory boards and/or as a speaker for Grifols and CSL Behring. He is on the board of directors of AlphaNet and serves as the Medical Director of AlphaNet. KEH has received consulting income from AlphaNet. RC has received research support from AlphaNet. TB reports no conflicts., (JCOPDF © 2021.)

The 2020 Global Initiative for Obstructive Lung Disease report indicates that the blood biomarker procalcitonin (PCT) may assist in decision-making regarding the initiation of antibiotics for chronic obstructive pulmonary disease (COPD) exacerbations. PCT is an acute-phase reactant that increases in response to inflammation and infection, and has been studied in various bacterial infections for initiation and de-escalation of antibacterials. The purpose of this systematic review and meta-analysis was to evaluate the strength of the data on the use of PCT to guide antibiotic prescription in COPD exacerbations. Among the randomized clinical trials included in our meta-analysis, almost all of which were conducted exclusively in the hospital setting. PCT was found to decrease overall antibiotic exposure in COPD exacerbations by 2.01 days (p = 0.04), while no apparent effects were found on clinical outcomes (length of hospital stay, p = 0.88; treatment failure p = 0.51; all-cause mortality p = 0.28). However, the majority of blood PCT levels in COPD exacerbations were below the manufacturer-recommended cutoff for antibiotics, and the use of this marker was associated with worse outcomes in the intensive care setting. Further, based on additional sensitivity analysis excluding studies with high risk of bias or with converted outcome value, the effect of PCT on antibiotic duration in RCTs was no longer significant (MD = -1.88 days, 95% CI [-3.95, 0.19] days, p = 0.08, and MD = -1.72 days, 95% CI [-4.28, 0.83] days, p = 0.19, respectively). Our review and analysis does not support the use of PCT to guide antibiotic prescription in COPD exacerbations.

The 2020 Global Initiative for Obstructive Lung Disease (GOLD) Report highlights the importance of sputum purulence in the decision to prescribe antibiotics for acute exacerbations. The purpose of this systematic review and meta-analysis was to evaluate the strength of literature supporting inclusion of sputum purulence in criteria utilized to evaluate if antimicrobials are indicated in acute COPD exacerbation. A total of 6 observational studies met inclusion criteria for this meta-analysis. Sputum purulence was defined by visual assessment of color, either subjectively by providers and/or patients or by a colored chart, where green or yellow sputum was considered purulent. Four of the studies were primarily conducted in hospitalized patients, one in the emergency department, and one in the primary care setting. Five studies relied upon expectorated sputum and one used bronchoscopy to obtain sputum samples for bacterial cultures. Compared with mucoid sputum, purulent sputum had a significantly higher probability of positive bacterial culture results (RR = 2.14, 95%CI [1.25, 3.67], p  = 0.006, moderate quality). For sensitivity analysis, after removal of studies losing 2 or more points from the New Castle-Ottawa scale, the effect value remained statistically significant. This systematic review and meta-analysis showed a moderate level of evidence that purulent sputum during COPD exacerbation, as defined by yellow or green color, is associated with a significantly higher probability of potentially pathogenic bacteria, supporting GOLD report and NICE recommendations.

Background: COPD guidelines report that systemic corticosteroids are preferred over inhaled corticosteroids in the treatment of exacerbations, but the inhaled route is considered to be an option., Objectives: To conduct a systematic review and meta-analysis regarding the efficacy and safety of inhaled corticosteroids for COPD exacerbations. The second objective was to provide pharmacologic and clinical perspectives of inhaled corticosteroids for COPD exacerbations., Methods: The primary outcome was a change in FEV 1 baseline versus the last measured value. Secondary outcomes were a change in (P aO 2 ) and (P aCO 2 ) baselines versus the last measured values; FEV 1 , P aO 2 , and P aCO 2 at 24 or 72 h; and hyperglycemia., Results: Each of the 9 studies included in the meta-analysis was conducted in subjects who were hospitalized and not critically ill. Our meta-analysis indicated that high-dose nebulized budesonide 4-8 mg/d was noninferior to systemic corticosteroids on the change in FEV 1 between baseline and the last measured value (mean difference of 0.05, 95% CI -0.01 to 0.12, P = .13) and P aCO 2 (mean difference of -1.14, 95% CI -2.56 to 0.27, P = .11) but of inferior efficacy for P aO 2 changes (mean difference of -1.46, 95% -2.75 to -0.16, P = .03). Hyperglycemia was less frequent with high-dose nebulized budesonide (risk ratio, 0.13; 95% CI 0.03-0.46; P = .002)., Conclusions: Based on our meta-analysis with a change in FEV 1 as the primary end point, high-dose nebulized budesonide was an acceptable alternative to systemic corticosteroids in hospitalized subjects with COPD exacerbations who were not critically ill. Additional well-designed prospective studies are needed in both the acute care and ambulatory settings. We provide perspective on how this evidence might be applied in clinical practice., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2018 by Daedalus Enterprises.)

Computed tomography (CT) lung density is an accepted biomarker for emphysema in alpha-1 antitrypsin deficiency (AATD), although concerns for radiation exposure limit its longitudinal use. Serum proteins associated with emphysema, particularly in early disease, may provide additional pathogenic insights. We investigated whether distinct proteomic signatures characterize the presence and progression of emphysema in individuals with severe AATD and normal forced expiratory volume in 1 second (FEV 1 ). QUANT itative lung CT U n M asking emphysema progression in AATD (QUANTUM-1) is a multicenter, prospective 3-year study of 49 adults with severe AATD and FEV 1 post-bronchodilator values (Post-BD) ≥ 80% predicted. All participants received chest CT, serial spirometry, and contributed to the serum biobank. Volumetric imaging display and analysis (VIDA) software defined the baseline 15 th percentile density (PD15) which was indexed to CT-derived total lung capacity (TLC). We measured 317 proteins using a multiplexed immunoassay (Myriad Discovery MAP ® panel) in 31 individuals with a complete dataset. We analyzed associations between initial PD15/TLC, PD15/TLC annual decline, body mass index (BMI), and protein levels using Pearson's product moment correlation. C-reactive protein (CRP), adipocyte fatty acid-binding protein (AFBP), leptin, and tissue plasminogen activator (tPA) were found to be associated with baseline emphysema and all but leptin were associated with emphysema progression after adjustments were made for age and sex. All 4 proteins were associated with BMI after further adjustment for multiple comparisons was made. The relationship between these proteins and BMI, and further validation of these findings in replicative cohorts require additional studies., Competing Interests: TB has received grants from the CHEST Foundation and the Alpha-1 Foundation. MGJ, AVA and CA have nothing to declare. HOC reports grants from Spiration Inc., and personal fees from Samsung, outside of the submitted work. JLB, SES, CLW, LMS, AB, MB, RAS and EKS have nothing to declare. JKS is a consultant to: Grifols, Shire, CSL Behring, Arrowhead Pharmaceuticals and reports research funding from the National Institutes of Health, the Alpha-1 Foundation, and CSL Behring. He is also a member of the Board of Directors of the Alpha-1 Foundation and a member of the Medical and Scientific Advisory Committees of the Alpha-1 Foundation and the COPD Foundation. BT has nothing to declare. CS has grants with Adverum, the Alpha-1 Foundation, CSL Behring, Grifols, and Baxalta/Shire and has consulted for Grifols, Adverum and CSL Behring in alpha-1 antitrypsin deficiency and has an equity interest in Abeona. Computed tomography (CT) lung density is an accepted biomarker for emphysema in alpha-1 antitrypsin deficiency (AATD), although concerns for radiation exposure limit its longitudinal use. Serum proteins associated with emphysema, particularly in early disease, may provide additional pathogenic insights. We investigated whether distinct proteomic signatures characterize the presence and progression of emphysema in individuals with severe AATD and normal forced expiratory volume in 1 second (FEV1). QUANTitative lung CT UnMasking emphysema progression in AATD (QUANTUM-1) is a multicenter, prospective 3-year study of 49 adults with severe AATD and FEV1 post-bronchodilator values (Post-BD) ≥ 80% predicted. All participants received chest CT, serial spirometry, and contributed to the serum biobank. Volumetric imaging display and analysis (VIDA) software defined the baseline 15th percentile density (PD15) which was indexed to CT-derived total lung capacity (TLC). We measured 317 proteins using a multiplexed immunoassay (Myriad Discovery MAP® panel) in 31 individuals with a complete dataset. We analyzed associations between initial PD15/TLC, PD15/TLC annual decline, body mass index (BMI), and protein levels using Pearson’s product moment correlation. C-reactive protein (CRP), adipocyte fatty acid-binding protein (AFBP), leptin, and tissue plasminogen activator (tPA) were found to be associated with baseline emphysema and all but leptin were associated with emphysema progression after adjustments were made for age and sex. All 4 proteins were associated with BMI after further adjustment for multiple comparisons was made. The relationship between these proteins and BMI, and further validation of these findings in replicative cohorts require additional studies.

Rationale: Several chronic obstructive pulmonary disease (COPD) studies have evaluated risk factors for emergency department (ED) visits or hospitalizations, and found insufficient data available about social and demographic factors that drive these behaviors. This U.S. study was designed to describe the characteristics of COPD patients with ED visits or a hospitalization and to investigate how often common COPD comorbidities are present in these individuals. Methods: Data for 7180 COPD patients regarding demographic factors, comorbidities, smoking status, and ED visits or hospitalization was obtained from the 2012 Behavioral Risk Factor Surveillance System (BRFSS) survey. Logistic regression analysis was used to adjust demographic factors and smoking status to model the correlation between patients with ED visits or hospitalizations and morbidities generating odds ratios (OR) and confidence intervals (CI). Results: Among diagnosed COPD patients in the BRFSS, 16.5% had ED visits or hospitalization in the previous year. These individuals were younger, had a lower socio-economic status (lower education, lower income, and more often unemployed) and 23.4% of the individuals could not visit a doctor because of the financial difficulties compared to 16.7% who had no visit ( p <0.0001 for all comparisons). The prevalence of comorbidities was higher in those with ED visits or hospitalization compared to those without. Conclusion: In a population representative of COPD patients, lower socio-economic status and higher comorbidities are associated with ED visits or hospitalization. Studies are needed to further elucidate the complex relationship between COPD, comorbidities, and ED visits or hospitalization., Competing Interests: Drs. Suchit Kumbhare, Tatsiana Beiko, and Susan R. Wilcox do not have conflicts of interest. Dr. Charlie Strange has current, past, or pending grants in COPD from the Alpha-1 Foundation, Baxter, CSL Behring, Entera Health, Grifols, and the National Institutes of Health. He consults for AstraZeneca, Boehringer-Ingelheim, CSL Behring, Grifols, PlasmaTech, PneumRx, Pulmonx, and Uptake Medical on COPD.

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disease that creates multiple unique phenotypes of chronic obstructive pulmonary disease. While bronchospasm, cough, dyspnea, and sputum production all occur with AATD, the phenotypic differences require a computed tomographic (CT) scan to decipher. The availability of augmentation therapy in the United States since 1989 has generated both controversy and evidence that informs the science of usual chronic obstructive pulmonary disease (COPD). Because of the predominance of emphysema in AATD, much of the best evidence concerning biomarkers of emphysema progression comes from this population. Imaging measurement of emphysema progression, impact of emphysema phenotypes on hyperinflation and dynamic hyperinflation, and correlation with traditional spirometric measures of COPD progression are required to understand the impact of AAT therapies. These studies are important for better understanding of usual COPD pathogenesis. Significantly, there are no adequately powered research studies to determine if augmentation therapy is helpful for the non-emphysema phenotypes of AATD. Specifically, phenotypes of chronic bronchitis, asthma predominant disease, and bronchiectasis will require targeted research studies to define optimal therapy., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)