Search

Alpha-1 antitrypsin deficiency (AATD) is an underrecognized condition with only a small minority of affected individuals diagnosed, long delays between initial symptoms and diagnosis, and evidence that affected individuals may see many physicians with suggestive symptoms before an initial diagnosis is made. In the context that failure to detect AATD confers harm and that specific therapy is currently available, there is a clear need for enhanced detection. Impediments to enhanced detection include inadequate knowledge about AATD by physicians caring for at-risk patients, inattention to guidelines that endorse testing, a sense of "therapeutic nihilism" among some physicians (i.e., the mistaken impression that, because specific therapy is unavailable, there is no imperative to diagnose), and concerns about the cost of testing. Various measures have been undertaken to address these impediments and to enhance detection, including educational programs, targeted detection programs (some with free and home-based confidential testing), and population-based and newborn screening pilot programs. The latter is not yet nationally endorsed for large-scale screening. Novel approaches are deploying features of the electronic medical record and of artificial intelligence to prompt testing in at-risk individuals. To the extent that underrecognition of AATD persists with stubbornly long, multiyear diagnostic delay intervals, none of the detection strategies deployed to date have been adequate. The path forward regards continued innovation with targeted detection approaches while efforts continue to assess the impact of population-based screening, hopefully toward ultimate endorsement on a broad national scale. [ABSTRACT FROM AUTHOR] more...

This article discusses a study that aimed to improve the detection of Alpha-1 Antitrypsin Deficiency (AATD) through provider education. A web-based education module was developed and deployed to healthcare providers, focusing on addressing barriers to screening for AATD. The study found that provider confidence in identifying high-risk patients for AATD improved after completing the module, and the rate of screening for AATD also increased. The study highlights the importance of targeted healthcare provider education in improving AATD detection and emphasizes the value of testing in high-risk individuals. [Extracted from the article] more...

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 highrisk 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. [ABSTRACT FROM AUTHOR] more...

Alpha-1 antitrypsin deficiency (AATD) is characterized by neutrophil-dominated inflammation resulting in emphysema. The cholesterol-rich neutrophil outer plasma membrane plays a central role in adhesion and subsequent transmigration to underlying tissues. This study aimed to investigate mechanisms of increased neutrophil adhesion in AATD and whether alpha-1 antitrypsin (AAT) augmentation therapy abrogates this effect. Plasma and blood neutrophils were donated by healthy controls (n = 20), AATD (n = 30), and AATD patients after AAT augmentation therapy (n = 6). Neutrophil membrane protein expression was investigated using liquid chromatography–tandem mass spectrometry. The effect of once-weekly intravenous AAT augmentation therapy was assessed by calcium fluorometric, μ-calpain, and cell adhesion assays. Decreased neutrophil plasma membrane cholesterol content (P = 0.03), yet increased abundance of integrin a-M (fold change 1.91), integrin α-L (fold change 3.76), and cytoskeletal adaptor proteins including talin-1 (fold change 4.04) were detected on AATD neutrophil plasma membrane fractions. The described inflammatory induced structural changes were a result of a more than twofold increased cytosolic calcium concentration (P = 0.02), leading to significant calcium-dependent μ-calpain activity (3.5-fold change; P = 0.005), resulting in proteolysis of the membrane cholesterol trafficking protein caveolin-1. Treatment of AAT-deficient individuals with AAT augmentation therapy resulted in increased caveolin-1 and membrane cholesterol content (111.8 ± 15.5 vs. 64.18± 7.8 μg/2x 107 cells before and after treatment, respectively; P = 0.02), with concurrent decreased neutrophil integrin expression and adhesion. Results demonstrate an auxiliary benefit of AAT augmentation therapy, evident by a decrease in circulating inflammation and controlled neutrophil adhesion. [ABSTRACT FROM AUTHOR] more...

AAT (alpha-1 antitrypsin) deficiency (AATD), characterized by low levels of circulating serine protease inhibitor AAT, results in emphysematous destruction of the lung. Inherited serum deficiency disorders, such as hemophilia and AATD, have been considered ideal candidates for gene therapy. Although viral vector-meditated transduction of the liver has demonstrated utility in hemophilia, similar success has not been achieved for AATD. The challenge for AAT gene therapy is achieving protective levels of AAT locally in the lung and mitigating potential liver toxicities linked to systemically administered viral vectors. Current strategies with ongoing clinical trials involve different routes of adeno-associated virus administrations, such as intramuscular and intrapleural injections, to provide consistent therapeutic levels from nonhepatic organ sites. Nevertheless, exploration of alternative methods of nonhepatic sourcing of AAT has been of great interest in the field. In this regard, pulmonary endothelium-targeted adenovirus vector could be a key technical mandate to achieve local augmentation of AAT within the lower respiratory tract, with the potential benefit of circumventing liver toxicities. In addition, incorporation of the CRISPR/Cas9 (CRISPR-associated protein 9) nuclease system into gene-delivery technologies has provided adjunctive technologies that could fully realize a one-time treatment for sustained, lifelong expression of AAT in patients with AATD. This review will focus on the adeno-associated virus- and adenoviral vector-mediated gene therapy strategies for the pulmonary manifestations of AATD and show that endeavoring to use genome-editing techniques will advance the current strategy to one fully compatible with direct human translation. [ABSTRACT FROM AUTHOR] more...

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). [ABSTRACT FROM AUTHOR] more...

Chronic obstructive pulmonary disease (COPD) is now well recognized to be a phenotypically heterogeneous disease, and this heterogeneity is underpinned by biological heterogeneity. An "endotype" is a group of patients who share the same observed characteristic(s) because of shared underlying biology, and the "endotype" concept has emerged as one way of bringing order to this phenotypic heterogeneity by focusing on its biological underpinnings. In principle, biomarkers can help identify endotypes and mark these specific groups of patients as suitable candidates for targeted biological therapies. Among the better-described endotypes of COPD are alpha-1 antitrypsin deficiency and eosinophilic COPD. Both of these endotypes have biomarkers and at least some evidence of preferential benefit from targeted therapy. Other biological pathways that may define endotypes of COPD include more general pathways of type 2 inflammation, IL-17-driven inflammation (due to autoimmunity or deposition of nanoparticulate carbon black), bacterial colonization, pathological alterations of the airway mucus gel, and others that are beyond the scope of this review. Whether these biological pathways ultimately are found to segregate patients into very distinct endotypes or subsets (like alpha-1 antitrypsin deficiency) or, instead, are present as "treatable traits" in various combinations is uncertain. However imperfect, the endotype concept forces a focus on heterogeneity at a biological level, and the development of biomarkers of biological heterogeneity should help advance the goal of developing new therapies for COPD. [ABSTRACT FROM AUTHOR] more...

Rationale: Alpha-1 antitrypsin deficiency, caused primarily by homozygosity for the Z allele of the SERPINA1 gene, is a well-established genetic cause of chronic obstructive pulmonary disease (COPD). Whether the heterozygous PiMZ genotype for alpha-1 antitrypsin confers increased risk for COPD has been debated.Objectives: We analyzed 8,271 subjects in the Genetic Epidemiology of COPD (COPDGene) Study, hypothesizing that PiMZ would independently associate with COPD and COPD-related phenotypes.Methods: The COPDGene Study comprises a multiethnic, cross-sectional, observational cohort of non-Hispanic white and African American current and former smokers with at least 10 pack-years of smoking who were enrolled for detailed clinical and genetic studies of COPD and COPD-related traits. We performed multivariate logistic regression analysis for moderate to severe COPD and assessed Pi genotype with other relevant covariates in models stratified by race. We analyzed quantitative characteristics on the basis of volumetric computed tomography with generalized linear models controlling for genotype, scanner type, and similar covariates.Results: White PiMZ COPDGene subjects had significantly lower lung function, FEV1 percent predicted (68 ± 28 vs. 75 ± 27; P = 0.0005), and FEV1/FVC ratio (0.59 ± 0.18 vs. 0.63 ± 0.17; P = 0.0008), as well as more radiographic emphysema (P = 0.001), than subjects without alpha-1 antitrypsin Z risk alleles. Similarly, African American PiMZ subjects had lower lung function, FEV1 percent predicted (65 ± 33 vs. 84 ± 25; P = 0.009) and FEV1/FVC (0.61 ± 0.21 vs. 0.71 ± 0.15; P = 0.03).Conclusions: In the COPDGene Study, we demonstrate that PiMZ heterozygous individuals who smoke are at increased risk for COPD and obstructive lung function impairment compared with Z-allele noncarriers, regardless of race. Although severe alpha-1 antitrypsin deficiency is uncommon in African Americans, our study adds further support for initial targeted detection of all subjects with COPD for alpha-1 antitrypsin deficiency, including African Americans. Clinical trial registered with www.clinicaltrials.gov (NCT00608784). [ABSTRACT FROM AUTHOR] more...

In the past five decades, alpha-1 antitrypsin deficiency has been the only known genetic cause of emphysema, yet it explains the genetics in only 1-2% of severe cases. Recently, mutations in telomerase genes were found to induce susceptibility to young-onset, severe, and familial emphysema at a frequency comparable to that of alpha-1 antitrypsin deficiency. Telomerase mutation carriers with emphysema report a family history of idiopathic pulmonary fibrosis, and both lung phenotypes show autosomal dominant inheritance within families. The data so far point to a strong gene-environment interaction that determines the lung disease type. In never-smokers, pulmonary fibrosis predominates, while smokers, especially females, are at risk for developing emphysema alone or in combination with pulmonary fibrosis. The telomere-mediated emphysema phenotype appears to have clinically recognizable features that are distinct from alpha-1 antitrypsin deficiency, and patients are prone to developing short telomere syndrome comorbidities that influence clinical outcomes. In animal models, telomere dysfunction causes alveolar epithelial stem cell senescence, which is sufficient to drive lung remodeling and recruit inflammation. Here, we review the implications of these discoveries for understanding emphysema biology as well as for patient care. [ABSTRACT FROM AUTHOR] more...

Alpha-1 antitrypsin deficiency (AATD) is a condition caused by the inheritance of two mutated SERPINA1 gene alleles. Individuals with AATD are at increased risk of injury to the liver and lungs. The pulmonary manifestations include precocious onset of pulmonary emphysema and bronchiectasis. For nearly three decades, treatment has been available to individuals with emphysema caused by AATD, but this therapy-augmentation of plasma and tissue alpha-1 antitrypsin levels by intravenous administration of human plasma-derived protein-was approved by regulatory authorities based on its biochemical efficacy. This therapy appears to slow the progression of emphysema in patients with AATD. The medical, patient, and regulatory communities have sought assurance that this expensive therapy provides measurable clinical benefit. Documenting such benefit has been difficult because of the slow progression of the underlying lung disease in AATD, the rarity of this genetic condition, and the lack of direct quantitative measurements of emphysema progression. Over the past decade, quantitative computed tomography (CT) densitometry of the lungs has been found to correlate with severity and progression of emphysema. The recent publication of a well-powered, masked, placebo-controlled study using CT densitometry to evaluate the effectiveness of augmentation therapy at slowing the progression of emphysema has provided some assurance of the clinical efficacy of this therapy. [ABSTRACT FROM AUTHOR] more...

Registrational trials in rare and orphan diseases present complexities related to the identification of subjects, recruitment, logistical hurdles incumbent with far-flung study sites, and end points that are often less well defined than are those used in more common illnesses. Alpha-1 antitrypsin deficiency is an orphan disease of genetic origin that carries the additional challenges of variable penetration and slow disease progression. Registrational trials of augmentation therapy using plasma-derived alpha-1 antitrypsin carry all of the above-noted burdens, as well as competition from commercially available augmentation therapy in many countries. [ABSTRACT FROM AUTHOR] more...

Alpha-1 antitrypsin deficiency (AATD) is characterized by low levels of circulating alpha-1 antitrypsin and an increased risk for emphysema, liver disease, and panniculitis. The reduced levels of alpha-1 antitrypsin in AATD predispose the lung to unopposed proteolytic activity, predominantly from neutrophil-derived proteases, chiefly neutrophil elastase. This leads to emphysema. The mechanisms subtending the liver disease are less well understood, but are probably due to a "gain-of function" inflammatory process in the liver, stoked by intracellular retention of aberrantly folded alpha-1 antitrypsin. The panniculitis associated with AATD is most likely due to unopposed proteolytic activity in the skin. Although AATD has been traditionally viewed as a condition arising from a protease-antiprotease imbalance in the lung, it is increasingly recognized that AATD is an inflammatory disorder, both in the lung and in the extrapulmonary manifestations associated with the condition. This inflammation is predominantly neutrophil driven, and there are several alpha-1 antitrypsin-related mechanisms involved in potentiating this neutrophilic response. The rationale for AAT augmentation therapy in AATD is classically based on restoring the antiprotease balance in the lung, but its beneficial effects may also be exerted systemically, further exposing the pathogenesis of AATD-related disease and indicating a potential usage for alpha-1 antitrypsin in other inflammatory conditions. [ABSTRACT FROM AUTHOR] more...

Biomarkers of pathogenesis in chronic obstructive pulmonary disease (COPD) can significantly accelerate drug development. In COPD related to alpha-1 antitrypsin deficiency, the role of neutrophil elastase and its inhibition by alpha-1 antitrypsin protein focused interest on elastin degradation and the development of pulmonary emphysema. Amino acids desmosine and isodesmosine are unique cross-links in mature elastin fibers and can serve as biomarkers of elastin degradation when measured in body fluids. This review gives a perspective on what has been learned by the earliest measurements of desmosine and isodesmosine followed by later studies using methods of increased sensitivity and specificity and the meaning for developing new therapies. Also included are brief statements on the biomarkers fibrinogen, CC-16, and Aa-Val-360 in COPD. [ABSTRACT FROM AUTHOR] more...

Alpha-1 antitrypsin (A1AT) is an acute-phase protein, and is best known as an inhibitor of the serine proteases, specifically, neutrophil elastase, proteinase 3, and cathepsin G. The discovery of the connection between inherited A1AT deficiency and emphysema resulted in the concept of a proteinase-antiproteinase imbalance to explain the pathogenic mechanisms of chronic obstructive pulmonary disease, as well as the concomitant development of augmentation therapy with plasma-purified human A1AT. This proteinase-antiproteinase imbalance concept has been difficult to prove, as no single mechanism can account for the complex pathology of chronic obstructive pulmonary disease. New studies have begun to characterize A1AT as an antiinflammatory and an immunoregulatory protein, independent of its antiprotease activity. We recently found that A1AT binds to free fatty acids, and it is this form of A1AT that induces the expression and release of angiopoietin-like protein 4, a protein associated with dyslipidemia and inflammation. This latter finding further strengthens the idea that describing A1AT therapy as antiserine protease is perhaps an oversimplification. The preliminary findings suggest that A1AT could be used for the management of diseases not necessarily related to inherited A1ATD, and points toward a need for more detailed investigations into the relationships between the concentration, structure, and function of A1AT protein. [ABSTRACT FROM AUTHOR] more...

The potential for increased chronic obstructive pulmonary disease (COPD) risk among PI MZ subjects was initially recognized decades ago. However, despite many studies of this topic, it has remained controversial whether such increased risk exists. Several recent studies in large populations strongly support increased risk for COPD among PI MZ subjects. This increased PI MZ risk will need to be understood in the context of other identified COPD genetic determinants and investigations of COPD phenotypic heterogeneity. [ABSTRACT FROM AUTHOR] more...

Alpha-1 antitrypsin deficiency (AATD) is a recognized genetic cause of rapidly progressive loss of lung function conventionally assessed by the decline in FEV1. However, there is less information concerning other physiological measures and the impact on quality of life. Data derived predominantly from the UK national registry show that AATD presents with various physiological phenotypes with differing clinical impact and progression. In general, the decline in quality of life is surprisingly slow despite rapid loss of lung function, which may reflect the benefits of centralized services for patients with AATD. Use of the new GOLD classification identifies patient characteristics that relate to mortality and disparate symptomatology despite similar spirometric impairment. [ABSTRACT FROM AUTHOR] more...

Alpha-1 antitrypsin deficiency is a widely underrecognized condition, with evidence of persisting long diagnostic delays and patients' frequent need to see multiple physicians before initial diagnosis. Reasons for underrecognition include inadequate understanding of alpha-1 antitrypsin deficiency by physicians and allied health care providers; failure to implement available, guideline-based practice recommendations; and the belief that effective therapy is unavailable. Multiple studies have described both the results of screening and targeted detection of individuals with alpha-1 antitrypsin deficiency, with both varying strategies employed to identify at-risk individuals and varying results of testing. Also, various strategies to enhance detection of affected individuals have been examined, including use of the electronic medical record to prompt testing and empowerment of allied health providers, especially respiratory therapists, to promote testing for alpha-1 antitrypsin deficiency. Such efforts are likely to enhance detection with the expected result that the harmful effects of delayed diagnosis can be mitigated. [ABSTRACT FROM AUTHOR] more...

Chronic obstructive pulmonary disease (COPD) is defined as airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with the inhalation of noxious gases, typically cigarette smoke. The protease-antiprotease paradigm suggests that the pathogenesis of COPD and emphysema is the result of an imbalance between enzymes that degrade the extracellular matrix within the lung and proteins that oppose this proteolytic activity. This review assesses the genetic evidence in support of protease-antiprotease imbalance in the pathogenesis of COPD. It also articulates why suppression of protease activity in alpha-1 antitrypsin deficiency may be insufficient to prevent the progression of COPD. Rather, alpha-1 antitrypsin deficiency may be better treated by small-molecules so reads molecules, RNA-silencing, and other strategies that target the protein misfolding and polymerization that cause the disease. [ABSTRACT FROM AUTHOR] more...

The neutrophil is a powerful cellular defender of the vulnerable interface between the environment and pulmonary tissues. This cell's potent weapons are carefully calibrated in the healthy state to maximize effectiveness in fighting pathogens while minimizing tissue damage and allowing for repair of what damage does occur. The three related chronic airway disorders of cystic fibrosis, non-cystic fibrosis bronchiectasis, and alpha-1 antitrypsin deficiency all demonstrate significant derangements of this homeostatic system that result in their respective pathologies. An important shared feature among them is the inefficient resolution of chronic inflammation that serves as a central means for neutrophil-driven lung damage resulting in disease progression. Examining the commonalities and divergences between these diseases in the light of their immunopathology is informative and may help guide us toward future therapeutics designed to modulate the neutrophil's interplay with the pulmonary environment. [ABSTRACT FROM AUTHOR] more...

Cystic fibrosis and alpha-1 antitrypsin (AAT) deficiency are two of the commonest lethal hereditary lung diseases affecting white individuals. Although having quite different phenotypic extrapulmonary presentations, the lung disease associated with these conditions is exemplified by a neutrophil-dominated inflammation in which neutrophil elastase plays a major role. In AAT deficiency the diminution of the anti-neutrophil elastase protection, due to diminished AAT levels in the lung, predisposes the lung to an unopposed neutrophil elastase attack, whereas, in cystic fibrosis, the levels of AAT and other antiproteases are normal, but the neutrophil elastase burden is so large that it overwhelms the normal anti-neutrophil elastase protection. With this as background, it seems logical to augment the anti-neutrophil elastase defenses of the lung in both conditions using exogenous AAT. The type of AAT, the route of administration, and the physiologic, radiologic, and clinical readouts for this type of therapy are discussed, along with the similarities and differences between the two conditions and their responses to AAT therapy. [ABSTRACT FROM AUTHOR] more...

Cystic fibrosis is predominantly an airway disease with marked bronchiectatic changes associated with inflammation, chronic colonization, and progressive airflow obstruction. The condition can be identified in childhood and monitored with detectable airway changes early in life while conventional spirometry remains in the normal range. Alpha-1 antitrypsin deficiency can also be detected early in life through blood spot and genetic testing and leads (in some) to the development of airflow obstruction and a predominant emphysema phenotype with bronchiectatic changes in about 30%. Early detection also allows the natural history of the pulmonary physiological changes to be determined. Chronic obstructive pulmonary disease is usually detected late in the disease process when significant damage has occurred. The condition consists of varying combinations of airway disease, bronchiectasis, colonization, and emphysema. Lessons learned from the physiological evolution of airway disease in cystic fibrosis and the emphysema of alpha-1 antitrypsin deficiency provide strategies to enable early detection of chronic obstructive pulmonary disease in general and its phenotypes. [ABSTRACT FROM AUTHOR] more...

Rationale: Alpha-1 antitrypsin deficiency (AATD) predisposes to chronic obstructive pulmonary disease, but is underrecognized. Oxygenation and exercise desaturation in individuals with AATD-associated chronic obstructive pulmonary disease has been sparsely studied. The Long-term Oxygen Treatment Trial (LOTT) permits comparing these features of individuals with AATD with alpha-1 antitrypsin-replete (called "usual chronic obstructive pulmonary disease") LOTT participants.Objectives: Compare demographic, clinical, baseline oxygenation, and exercise desaturation features in participating AATD subjects with those of other LOTT subjects.Methods: LOTT is a multicenter randomized controlled trial comparing use of supplemental oxygen versus not in subjects with chronic obstructive pulmonary disease and moderate hypoxemia (resting oxygen saturation as measured by pulse oximetry, 89-93%) or normal oxygen saturation at rest and significant exercise desaturation.Measurement and Main Results: Among the 597 LOTT participants with nonmissing alpha-1 antitrypsin levels, 11 (1.8%) had severe AATD and 44 (7.4%) had mild/moderate AATD. Comparison of the 11 severely AAT-deficient individuals with the 542 LOTT participants with usual chronic obstructive pulmonary disease showed that the AATD subjects were younger and despite less smoking, had lower FEV1/FVC (mean post-bronchodilator FEV1/FVC, 0.38 ± 0.06 vs. 0.46 ± 0.13; P = 0.002). Comparison with 27 age-, sex-, and FEV1-matched alpha-1 antitrypsin-normal LOTT participants showed no baseline difference in resting room air pulse oximetry saturation (AATD, 93.6% ± 2.3% vs. 92.7% ± 2.2%; P = 0.64). Exercise-related desaturation was more severe in the individuals with AATD based on desaturation to 88% or less sooner during a 6-minute-walk test, having a higher percentage of desaturation points (e.g., <90%) during exercise, and having a higher distance-saturation product (defined as the distance walked in 6 min multiplied by the nadir saturation achieved during the 6-minute-walk test).Conclusions: These data suggest that individuals with AATD experience more profound desaturation with exercise than age-, sex-, race-, and FEV1-matched control subjects with usual chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00692198). [ABSTRACT FROM AUTHOR] more...