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.

Identification of male COPD patients with exertional hypoxemia who may benefit from long-term oxygen therapy.

Several studies have documented increased exercise capacity with supplemental oxygen therapy in patients with COPD and exertional hypoxemia, but a large trial failed to demonstrate a survival benefit in this population. Due to the heterogeneity observed in therapeutic responses, we sought to retrospectively evaluate survival in male COPD patients with exertional hypoxemia who had a clinically meaningful improvement in exercise capacity while using supplemental oxygen compared to their 6-minute walk test distance (6MWD) while walking on room air. We defined them as responders or non-responders based on a change in 6MWD of greater or less than 54m. We compared their clinical and physiologic characteristics, and their survival over time. From 817 COPD subjects who underwent an assessment for home oxygen during the study period, 140 met inclusion criteria, with 70 (50%) qualifying as responders. There were no significant differences in demographics, lung function, or baseline oxygenation between the groups. The only difference noted was in the baseline 6MWD on room air, with responders to oxygen therapy having significantly lower values (137 ± 74m, 27 ± 15% predicted) compared to non-responders (244 ± 108, 49 ± 23% predicted). Despite their poorer functional capacity, mortality was significantly lower in responders after adjusting for age, comorbidities, and FEV1 (HR 0.51; CI 0.31-0.83; p = 0.007) compared to non-responders after a median follow-up time of 3 years. We conclude that assessing the immediate effects of oxygen on exercise capacity may be an important way to identify individuals with exertional hypoxemia who may benefit in the long-term from ambulatory oxygen. Prospective long-term studies in this subset of patients with exercise induced hypoxemia are warranted.

The Impact of Yoga on Inspiratory Muscle Performance in Veterans with COPD: A Pilot Study.

Chronic obstructive pulmonary disease (COPD) causes respiratory muscle weakness that leads to disabling dyspnea and poor functional performance. Therapies are often geared to improve inspiratory muscle performance. Yoga has been shown to improve exercise capacity, quality of life, and some pulmonary function measures in COPD, but little research has examined the effects of yoga training on inspiratory muscle performance. The purpose of this study was to investigate the effects of yoga training on inspiratory muscle performance in military veterans using the Test of Incremental Respiratory Endurance (TIRE). A prospective pilot study examined a 6-week yoga training program consisting of asana (poses) and pranayama (controlled breathing). Subjects had baseline inspiratory muscle weakness. The TIRE measured inspiratory muscle performance via the PrO2 device, providing maximal inspiratory pressure, sustained maximal inspiratory pressure, and inspiratory duration. Secondary measures included 6-minute walk distance, St. George Respiratory Questionnaire, Hospital Anxiety and Depression Scale, and spirometry. Mean age and BMI of subjects were 67 ± 3.6 years and 20.7 ± 3.3, respectively. The majority of subjects had severe (28.7%) or very severe (57.1%) COPD. Statistically significant improve m e n t s were seen in maximal inspiratory pressure (39.0 ± 14.1 cmH2O to 56.4 ± 20.6 cmH2O) and sustained maximal inspiratory pressure (244.1 ± 100.6 PTU to 308.1 ± 121.2 PTU). No statistically significant improvements we re observed in 6-minute walk distance, St. George Respiratory Questionnaire, Hospital Anxiety and Depression Scale, or spirometry. Yoga training has the potential in improve inspiratory muscle performance in veterans with severe to very severe COPD who present with inspiratory muscle weakness. This is of importance because improving inspira-tory muscle performance has been shown to improve COPD outcomes.

A 28-day clinical trial of aerosolized hyaluronan in alpha-1 antiprotease deficiency COPD using desmosine as a surrogate marker for drug efficacy.

INTRODUCTION: A previous 2-week clinical trial of aerosolized hyaluronan (HA) in COPD showed a rapid reduction in lung elastic fiber breakdown, as measured by sputum levels of the unique elastin crosslinks, desmosine and isodesmosine (DID). To further assess the therapeutic efficacy of HA and the utility of DID as surrogate markers for the development of pulmonary emphysema, we have conducted a 28-day randomized, double-blind, placebo-controlled, phase 2 trial of HA involving 27 subjects with alpha-1 antiprotease deficiency COPD. METHODS: The study drug consisted of a 3 ml inhalation solution containing 0.03% HA with an average molecular weight of 150 kDa that was self-administered twice daily. DID levels were measured in urine, sputum, and plasma using tandem mass spectrometry. RESULTS: Free urine DID in the HA group showed a significant negative correlation with time between days 14 and 35 (r = -1.0, p = 0.023) and was statistically significantly decreased from baseline at day 35 (15.4 vs 14.2 ng/mg creatinine, p = 0.035). A marked decrease in sputum DID was also seen in the HA group between days 1 and 28 (0.96 vs 0.18 ng/mg protein), but the difference was not significant, possibly due to the small number of adequate specimens. Plasma DID remained unchanged following HA treatment and no significant reductions in urine, sputum, or plasma DID were seen in the placebo group. CONCLUSIONS: The results support additional clinical trials to further evaluate the therapeutic effect of HA and the use of DID as a real-time marker of drug efficacy.

State-Level Disparity in Lung Cancer Survival in the United States.

Rationale: The cancer mortality-to-incidence ratio (MIR) can serve as a population-based indicator for cancer care outcomes. In the US, evaluation of lung cancer survival by individual states has not been evaluated. Objective: To assess the association between lung cancer survival by using MIRs and state-level health disparities in the United States. Methods: We calculated 5-year lung cancer MIR averages from 2011 to 2015 using the United States Cancer Statistics (USCS) data. America's Health Rankings (AHR) is a platform using weighted measures in five different categories to calculate annual state health rankings. Five-year averages from 2011 to 2015 of the health uninsured rate and 4-year averages from 2011 to 2014 of health spending per capita were obtained from the U.S. Census Bureau and Centers for Medicare & Medicaid Services. Linear regression analyses were performed to determine the associations between cancer survival value (CSV) = (1 - MIR) × 100% and state health variables. Results: During the study period, the 5-year averages of age-adjusted incidence, mortality rates, and CSVs were 60.3 ± 2.1 per 100,000 population, 43.4 ± 2.1 per 100,000, and 27.9 ± 3.9%, respectively. Among the 50 states, Connecticut had the highest CSV (38.6 ± 1.7%) whereas Nevada had the lowest CSV (18.7 ± 6.5%). Hawaii had the highest health ranking and Mississippi had the lowest ranking in 2016. States with better health rankings, lower health uninsured rates, and higher health spending were significantly associated with higher CSVs (R 2 = 0.418, P < 0.001; R 2 = 0.352, P < 0.001; R 2 = 0.142, P = 0.007, respectively). Conclusions: There are significant differences in lung cancer survival within the United States. Lung cancer survival by using CSV was strongly associated with state health disparities, and it can be an applicable measure to evaluate the state-level health disparities in the United States.

Long Noncoding Transcriptome in Chronic Obstructive Pulmonary Disease.

Chronic airway inflammation from recurring exposures to noxious environmental stimuli results in a progressive and irreversible airflow limitation and the lung parenchymal damage that characterizes chronic obstructive pulmonary disease (COPD). The large variability observed in the onset and progression of COPD is primarily driven by complex gene-environment interactions. The transcriptomic and epigenetic memory potential of lung epithelial and innate immune cells drive responses, such as mucus hyperreactivity and airway remodeling, that are tightly regulated by various molecular mechanisms, for which several candidate susceptibility genes have been described. However, the recently described noncoding RNA species, in particular the long noncoding RNAs, may also have an important role in modulating pulmonary responses to chronic inhalation of toxic substances and the development of COPD. This review outlines the features of long noncoding RNAs that have been implicated in regulating the airway inflammatory responses to cigarette smoke exposure and their possible association with COPD pathogenesis. As COPD continues to debilitate the increasingly aging population and contribute to higher morbidity and mortality rates worldwide, the search for better biomarkers and alternative therapeutic options is pivotal.

The Biological Effects of Double-Dose Alpha-1 Antitrypsin Augmentation Therapy. A Pilot Clinical Trial.

Rationale: Augmentation therapy with intravenous AAT (alpha-1 antitrypsin) is the only specific therapy for individuals with pulmonary disease from AAT deficiency (AATD). The recommended standard dose (SD; 60 mg/kg/wk) elevates AAT trough serum levels to around 50% of normal; however, outside of slowing emphysema progression, its effects in other clinical outcomes have not been rigorously proven.Objectives: To evaluate the biological effects of normalizing AAT trough levels with double-dose (DD) therapy (120 mg/kg/wk) in subjects with AATD already receiving SD therapy.Methods: Clinically stable subjects were evaluated after 4 weeks of SD therapy, followed by 4 weeks of DD therapy, and 4 weeks after return to SD therapy. At the end of each phase, BAL fluid (BALF) and plasma samples were obtained.Measurements and Main Results: DD therapy increased trough AAT levels to normal and, compared with SD therapy, reduced serine protease activity in BALF (elastase and cathepsin G), plasma elastase footprint (Aα-Val360), and markers of elastin degradation (desmosine/isodesmosine) in BALF. DD therapy also further downregulated BALF ILs and cytokines including Jak-STAT (Janus kinases-signal transducer and activator of transcription proteins), TNFα (tumor necrosis factor-α), and T-cell receptor signaling pathways, cytokines involved in macrophage migration, eosinophil recruitment, humoral and adaptive immunity, neutrophil activation, and cachexia. On restarting SD after DD treatment, a possible carryover effect was seen for several biological markers.Conclusions: Subjects with AATD on SD augmentation therapy still exhibit inflammation, protease activity, and elastin degradation that can be further improved by normalizing AAT levels. Higher AAT dosing than currently recommended may lead to enhanced clinical benefits and should be explored further.Clinical trial registered with www.clinicaltrials.gov (NCT01669421).

Higher serum levels of systemic inflammatory markers are linked to greater inspiratory muscle dysfunction in COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with an inflammatory response that becomes more pronounced in acute exacerbations. Considerable attention has recently focused on the value of several inflammatory mediators in predicting worsening of COPD-related symptoms. Whereas respiratory muscle dysfunction is also widely present in this population, little is known about how systemic inflammation relates to inspiratory muscle dysfunction in COPD. METHODS: Fifty-three males with mild-to-very severe airflow obstruction underwent blood sampling for 23 inflammatory markers, including acute-phase proteins, cytokines and adipokines. Inspiratory muscle performance was assessed via the test of incremental respiratory endurance, providing measures of maximal (MIP) and sustained maximal (SMIP) inspiratory pressures. RESULTS: The mean ± SD MIP and SMIP were 75.32 ± 19.62 cmH2 O and 406.15 ± 124.55 PTU. MIP negatively correlated with CRP, SAA and cystatin C (r-values from -0.333 to -0.378, P < 0.02), while SMIP was inversely related to SAA and cystatin C (r = -0.534 and r = -0.396, P = 0.00). Significant differences in CRP, SAA, cystatin C and PARC were also found between subjects with and without inspiratory muscle weakness. No additional significant relationships were observed between either MIP or SMIP and other inflammatory markers in the study. CONCLUSIONS: MIP and SMIP are markedly reduced with greater degrees of inflammation in COPD as expressed by higher levels of CRP, SAA and cystatin C. Future research is needed to further examine the above findings and determine the impact of systemic inflammation along with its underlying mechanisms on inspiratory muscle function in COPD.

Beyond inspiratory muscle strength: Clinical utility of single-breath work capacity assessment in veterans with COPD.

BACKGROUND: Inspiratory muscle function in COPD has been traditionally described in terms of maximal inspiratory pressure (MIP). Arguably, however, is the day-to-day relevance of MIP, given that individuals rarely need maximal inspiratory forces to perform general tasks, but rather repeated breathing muscle contractions which demand endurance. The sustained maximal inspiratory pressure (SMIP) reflects the ability of the respiratory muscles to maintain force over time (i.e. single-breath work capacity). We investigated the relationships between SMIP and COPD-related clinical outcomes, hypothesizing that SMIP would have superior correlational and discriminatory value when compared to MIP. METHODS: 61 males with mild-to-very severe airflow obstruction underwent measures of spirometry, whole-body plethysmography, symptomatology, comorbidity, quality of life, exacerbations and mental health. MIP and SMIP were obtained via the Test of Incremental Respiratory Endurance. RESULTS: The mean ±â€¯SD MIP and SMIP were 77.2 ±â€¯22.9 cmH2O and 407.9 ±â€¯122.8 PTU. Both MIP and SMIP positively correlated with pulmonary function, with SMIP displaying the highest correlations. We found significant differences in spirometry, hyperinflation, symptomatology, exacerbation frequency, comorbidity, quality of life and anxiety in subjects grouped as having reduced or normal single-breath work capacity. Finally, significantly lower SMIP values were found in individuals with an IC/TLC ratio ≤25%. CONCLUSIONS: The assessment of SMIP appears to have superior clinical value than MIP in COPD. Our analyses revealed that subjects whose SMIP was reduced experienced more severe airflow obstruction, greater hyperinflation, as well as worse health and mental status with increased symptomatology and impaired quality of life.

ROLE OF GENETIC SUSCEPTIBILITY IN NICOTINE ADDICTION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in developed countries. Although cigarette smoking is the major risk factor, only 10-20% of smokers develop COPD. The extent of cigarette smoking (pack-years and smoking duration) accounts for only 15% of the variation in lung function, indicating that differences in susceptibility to COPD must exist. We provide an overview of the complexity of nicotine addiction and COPD, with special attention to the involvement of genetic factors. The following aspects are discussed in the present article: (1) epidemiology in Mexico and (2) a review of the published literature on genetic association studies using the National Center for Biotechnology Information database of the United States as a search tool. COPD is unique among complex genetic diseases where an environmental risk factor is known and the level of exposure can be documented with some precision. The high morbidity and mortality associated with COPD and its chronic and progressive nature has prompted the use of molecular genetic studies to identify susceptibility factors for the disease. Biomedical research has a remarkable set of tools to aid in the discovery of genes and polymorphisms. We present a review of the most relevant genetic associations in nicotine addiction and COPD.

Role of genetic susceptibility in nicotine addiction and chronic obstructive pulmonary disease

Abstract Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in developed countries. Although cigarette smoking is the major risk factor, only 10-20% of smokers develop COPD. The extent of cigarette smoking (pack-years and smoking duration) accounts for only 15% of the variation in lung function, indicating that differences in susceptibility to COPD must exist. We provide an overview of the complexity of nicotine addiction and COPD, with special attention to the involvement of genetic factors. The following aspects are discussed in the present article: (1) epidemiology in Mexico and (2) a review of the published literature on genetic association studies using the National Center for Biotechnology Information database of the United States as a search tool. COPD is unique among complex genetic diseases where an environmental risk factor is known and the level of exposure can be documented with some precision. The high morbidity and mortality associated with COPD and its chronic and progressive nature has prompted the use of molecular genetic studies to identify susceptibility factors for the disease. Biomedical research has a remarkable set of tools to aid in the discovery of genes and polymorphisms. We present a review of the most relevant genetic associations in nicotine addiction and COPD.

The BODE index and inspiratory muscle performance in COPD: Clinical findings and implications.

OBJECTIVES: The Test of Incremental Respiratory Endurance is a novel testing method that provides a unique examination of one's inspiratory muscle strength, work and endurance. Little is known about the relationship between inspiratory muscle performance and mortality risk in obstructive lung disease. We examined the relationship between the Test of Incremental Respiratory Endurance measures and the Body-mass index, airflow Obstruction, Dyspnea and Exercise index in chronic obstructive pulmonary disease. METHODS: In all, 70 males with mild-to-very severe chronic obstructive pulmonary disease (mean ± standard deviation of 70.2 ± 5.9 years) underwent measurements of body-mass index, spirometry, dyspnea and a 6-min walk test from which the Body-mass index, airflow Obstruction, Dyspnea and Exercise score was calculated. The Test of Incremental Respiratory Endurance provided measures of maximal inspiratory pressure, sustained maximal inspiratory pressure and inspiratory duration. RESULTS: All Test of Incremental Respiratory Endurance parameters inversely correlated with the Body-mass index, airflow Obstruction, Dyspnea and Exercise score: maximal inspiratory pressure (r = -0.355, p = 0.00), sustained maximal inspiratory pressure (r = -0.426, p = 0.00) and ID (r = -0.278, p = 0.02), with sustained maximal inspiratory pressure displaying the highest correlation. Independent significant correlations were also observed between the sustained maximal inspiratory pressure and all Body-mass index, airflow Obstruction, Dyspnea and Exercise score components, except for body-mass index. Finally, sustained maximal inspiratory pressure was significantly different among the Body-mass index, airflow Obstruction, Dyspnea and Exercise index quartiles. DISCUSSION: The significant association between the Body-mass index, airflow Obstruction, Dyspnea and Exercise score and inspiratory muscle performance, in particular sustained maximal inspiratory pressure, suggests that these measures may have a potential prognostic value in the evaluation of chronic obstructive pulmonary disease.

Reliability and validity of the test of incremental respiratory endurance measures of inspiratory muscle performance in COPD.

Purpose: The Test of Incremental Respiratory Endurance (TIRE) provides a comprehensive assessment of inspiratory muscle performance by measuring maximal inspiratory pressure (MIP) over time. The integration of MIP over inspiratory duration (ID) provides the sustained maximal inspiratory pressure (SMIP). Evidence on the reliability and validity of these measurements in COPD is not currently available. Therefore, we assessed the reliability, responsiveness and construct validity of the TIRE measures of inspiratory muscle performance in subjects with COPD. Patients and methods: Test-retest reliability, known-groups and convergent validity assessments were implemented simultaneously in 81 male subjects with mild to very severe COPD. TIRE measures were obtained using the portable PrO2 device, following standard guidelines. Results: All TIRE measures were found to be highly reliable, with SMIP demonstrating the strongest test-retest reliability with a nearly perfect intraclass correlation coefficient (ICC) of 0.99, while MIP and ID clustered closely together behind SMIP with ICC values of about 0.97. Our findings also demonstrated known-groups validity of all TIRE measures, with SMIP and ID yielding larger effect sizes when compared to MIP in distinguishing between subjects of different COPD status. Finally, our analyses confirmed convergent validity for both SMIP and ID, but not MIP. Conclusion: The TIRE measures of MIP, SMIP and ID have excellent test-retest reliability and demonstrated known-groups validity in subjects with COPD. SMIP and ID also demonstrated evidence of moderate convergent validity and appear to be more stable measures in this patient population than the traditional MIP.

Impact of a Health Management Program on Healthcare Outcomes among Patients on Augmentation Therapy for Alpha 1-Antitrypsin Deficiency: An Insurance Claims Analysis.

INTRODUCTION: Alpha 1-antitrypsin deficiency (AATD) is a genetic disorder which reduces serum alpha 1-antitrypsin (AAT or alpha1-proteinase inhibitor, A1PI) and increases the risk of chronic obstructive pulmonary disease (COPD). Management strategies include intravenous A1PI augmentation, and, in some cases, a health management program (Prolastin Direct®; PD). OBJECTIVES: This study compared clinical and economic outcomes between patients with and without PD program participation. METHODS: This retrospective study included commercial and Medicare Advantage health insurance plan members with ≥ 1 claim with diagnosis codes for COPD and ≥ 1 medical or pharmacy claim including A1PI (on index date). Outcomes were compared between patients receiving only Prolastin® or Prolastin®-C (PD cohort) and patients who received a different brand without PD (Comparator cohort). Demographic and clinical characteristics were captured during 6 months pre-index. Post-index exacerbation episodes and healthcare utilization and costs were compared between cohorts. RESULTS: The study sample comprised 445 patients (n = 213 in PD cohort; n = 232 in Comparator cohort), with a mean age 55.5 years, 50.8% male, and 78.9% commercially insured. The average follow-up was 822 days (2.25 years), and the average time on A1PI was 747 days (2.04 years). Few differences were observed in demographic or clinical characteristics. Adjusting for differences in patient characteristics, the rate of severe exacerbation episodes was reduced by 36.1% in the PD cohort. Adjusted total annual all-cause costs were 11.4% lower, and adjusted mean respiratory-related costs were 10.6% lower in the PD cohort than the Comparator cohort. Annual savings in all-cause total costs in the PD cohort relative to the Comparator cohort was US$25,529 per patient, largely due to significantly fewer and shorter hospitalizations. CONCLUSIONS: These results suggest that comprehensive health management services may improve both clinical and economic outcomes among patients with COPD and AATD who receive augmentation therapy. FUNDING: Grifols Shared Services of North America, Inc.

Differences in vaping topography in relation to adherence to exclusive electronic cigarette use in veterans.

BACKGROUND: Understanding vaping patterns of electronic cigarette (EC) use is important to understand the real-life exposure to EC vapor. Long term information on vaping topography in relation to tobacco cigarette (TC) smoking cessation success has not been explored. METHODS: Observational non-blinded study where active TC smokers were asked to replace TC with EC over 4 weeks (replacement phase, RP) followed by exclusive EC use for an additional 12 weeks (maintenance phase, MP). TC use and EC compliance was monitored weekly. Subjects were classified as success or failure whether or not they completed the protocol. Vaping information was stored and downloaded directly from the EC device and averaged per calendar day for analysis. RESULTS: From 25 subjects that followed the protocol, sixteen succeeded in completing the RP and 8 the MP (32%). No significant differences in baseline characteristics were noted between subjects in the success and failure groups including markers of nicotine addiction, plasma cotinine levels or smoking history. Success subjects showed significantly longer puff duration (seconds per vape) and total overall vapor exposure (number of vapes x average vape duration or vape-seconds) in both study phases. Furthermore, subjects in the success group continued to increase the number of vapes, device voltage and wattage significantly as they transitioned into the MP. After an initial drop, subjects in the success group were able to regain plasma cotinine levels comparable to their TC use while subjects in the failure group could not. Cotinine levels significantly correlated with the average number of daily vapes and vapes-seconds, but not with other vaping parameters. CONCLUSION: The topography of smokers who adhere to exclusive EC use reflects a progressive and dynamic device adaptation over weeks to maintain baseline cotinine levels. The higher inhaled volume over time should be considered when addressing the potential toxic effects of EC and the variable EC adherence when addressing public health policies regarding their use.

Inspiratory Muscle Performance of Former Smokers and Nonsmokers Using the Test of Incremental Respiratory Endurance.

BACKGROUND: Smoking has potential deleterious effects on respiratory muscle function. Smokers may present with reduced inspiratory muscle strength and endurance. We compared inspiratory muscle performance of nonsmokers with that of former smokers without overt respiratory problems via the Test of Incremental Respiratory Endurance. METHODS: This study was performed on 42 healthy subjects between the ages of 30 and 79 y (mean ± SD of 56.5 ± 14.4 y). Fourteen male and 7 female former smokers were matched to nonsmokers based on sex, age, height, and weight. Subjects completed a questionnaire about their health and current smoking status. Testing included the best of 3 or more consistent trials. The Test of Incremental Respiratory Endurance measurements included maximal inspiratory pressure measured from residual volume as well as sustained maximal inspiratory pressure and inspiratory duration measured from residual volume to total lung capacity during a maximal sustained inhalation. RESULTS: No significant difference in inspiratory performance of the entire group of former smokers compared with nonsmokers was found. However, separate sex analyses found a significant difference in sustained maximal inspiratory pressure between male former smokers and nonsmokers (518.7 ± 205.0 pressure time units vs 676.5 ± 255.2 pressure time units, P = .041). CONCLUSIONS: We found similar maximal inspiratory pressure between former smokers and nonsmokers via the Test of Incremental Respiratory Endurance, but the significant difference in sustained maximal inspiratory pressure between male former smokers and nonsmokers suggests that the sustained maximal inspiratory pressure may have greater discriminatory ability in assessing the effects of smoking on inspiratory muscle performance. Further investigation of the effects of smoking on inspiratory performance via the Test of Incremental Respiratory Endurance is warranted.

The Role of Computed Tomography for the Evaluation of Lung Disease in Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is characterized by low serum levels of or dysfunctional alpha-1 proteinase inhibitor. In the lung parenchyma, this results in a loss of protection against the activity of serine proteases, particularly neutrophil elastase. The resultant imbalance in protease and antiprotease activity leads to an increased risk for the development of early-onset emphysema and COPD. As in traditional smoke-related COPD, the assessment of the severity and disease progression of lung disease in AATD is conventionally based on lung function; however, pulmonary function tests are unable to discriminate between emphysema and airways disease, the two hallmark pathologic features of COPD. CT imaging has been used as a tool to further characterize lung structure and evaluate therapeutic interventions in AATD-related COPD. Moreover, recent advances in quantitative CT have significantly improved our assessment of the lung architecture, which has provided investigators and clinicians with a more detailed evaluation of the extent and severity of emphysema and airways disease in AATD. In addition, serial CT imaging measures are becoming increasingly important, as they provide a tool to monitor emphysema progression. This review describes the principles of CT technology and the role of CT imaging in assessing pulmonary disease progression in AATD, including the effect of therapeutic interventions.

Bioequivalence of a Liquid Formulation of Alpha1-Proteinase Inhibitor Compared with Prolastin®-C (Lyophilized Alpha1-PI) in Alpha1-Antitrypsin Deficiency.

This study evaluated the bioequivalence, safety, and immunogenicity of a new liquid formulation of human plasma-derived alpha1-proteinase inhibitor, Liquid Alpha1-PI, compared with the Lyophilized Alpha1-PI formulation (Prolastin®-C), for augmentation therapy in patients with alpha1-antitrypsin deficiency (AATD). In this double-blind, randomized, 20-week crossover study, 32 subjects with AATD were randomized to receive 8 weekly infusions of 60 mg/kg of Liquid Alpha1-PI or Lyophilized Alpha1-PI. Serial blood samples were drawn for 7 days after the last dose followed by 8 weeks of the alternative treatment. The primary endpoint was bioequivalence at steady state, as measured by area under the concentration versus time curve from 0 to 7 days (AUC0-7 days) postdose using an antigenic content assay. Bioequivalence was defined as 90% confidence interval (CI) for the ratio of the geometric least squares (LS) mean of AUC0-7 days for both products within the limits of 0.80 and 1.25. Safety and immunogenicity were assessed. Mean alpha1-PI concentration versus time curves for both formulations were superimposable. Mean AUC0-7 days was 20 320 versus 19 838 mg × h/dl for Liquid Alpha1-PI and Lyophilized Alpha1-PI, respectively. The LS mean ratio of AUC0-7 days (90% CI) for Liquid Alpha1-PI versus Lyophilized Alpha1-PI was 1.05 (1.03-1.08), indicating bioequivalence. Liquid Alpha1-PI was well tolerated and adverse events were consistent with Lyophilized Alpha1-PI. Immunogenicity to either product was not detected. In conclusion, Liquid Alpha1-PI is bioequivalent to Lyophilized Alpha1-PI, with a similar safety profile. The liquid formulation would eliminate the need for reconstitution and shorten preparation time for patients receiving augmentation therapy for AATD.

The important role of primary care providers in the detection of alpha-1 antitrypsin deficiency.

OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is an underrecognized genetic disorder that can cause chronic obstructive pulmonary disease (COPD) and liver cirrhosis, two clinical conditions commonly seen by primary care physicians. AATD is estimated to affect 1/4000-1/5000 people in the United States and 1-2% of all COPD cases. METHODS: PubMed was searched for relevant articles using AAT/AATD-related terms. RESULTS: Unfortunately, <10% of symptomatic individuals have been properly diagnosed primarily due to the underdiagnosis of COPD and the lack of awareness of AATD as a possible underlying cause. Because primary care providers are most likely to be the first to encounter symptomatic individuals, their role in the identification and early diagnosis of AATD patients is instrumental, particularly since therapy to slow lung disease progression is available. The diagnosis of AATD is laboratory-based rather than clinical. Testing for AATD should be part of the reflex testing that follows any COPD diagnosis or unexplained liver disease and can be performed by determining the AAT phenotype or genotype along with serum AAT levels. Both nonpharmacological and pharmacological approaches are recommended for treatment of lung disease, including smoking cessation, bronchodilators or supplemental oxygen as needed. Specific augmentation of AAT levels with regular purified AAT infusions has been found to slow lung function decline and emphysema progression in patients with moderate airflow obstruction and severely low serum AAT levels. CONCLUSIONS: Improving primary care provider awareness and promoting regular reflex testing all COPD patients for AATD may significantly improve the care of COPD patients.