Usual Chronic Obstructive Pulmonary Disease Research Articles

Cardiovascular disease in Alpha 1 antitrypsin deficiency: an observational study assessing the role of neutrophil proteinase activity and the suitability of validated screening tools

BackgroundAlpha 1 Antitrypsin Deficiency (AATD) is a rare, inherited lung disease which shares features with Chronic Obstructive Pulmonary Disease (COPD) but has a greater burden of proteinase related tissue damage. These proteinases are associated with cardiovascular disease (CVD) in the general population. It is unclear whether patients with AATD have a greater risk of CVD compared to usual COPD, how best to screen for this, and whether neutrophil proteinases are implicated in AATD-associated CVD. This study had three aims. To compare CVD risk in never-augmented AATD patients to non-AATD COPD and healthy controls (HC). To assess relationships between CVD risk and lung physiology. To determine if neutrophil proteinase activity was associated with CVD risk in AATD. Cardiovascular risk was assessed by QRISK2® score and aortic stiffness measurements using carotid-femoral (aortic) pulse wave velocity (aPWV). Medical history, computed tomography scans and post-bronchodilator lung function parameters were reviewed. Systemic proteinase 3 activity was measured. Patients were followed for 4 years, to assess CVD development.Results228 patients with AATD, 50 with non-AATD COPD and 51 healthy controls were recruited. In all COPD and HC participants, QRISK2® and aPWV gave concordant results (with both measures either high or in the normal range). This was not the case in AATD. Once aPWV was adjusted for age and smoking history, aPWV was highest and QRISK2® lowest in AATD patients compared to the COPD or HC participants. Higher aPWV was associated with impairments in lung physiology, the presence of emphysema on CT scan and proteinase 3 activity following adjustment for age, smoking status and traditional CVD risk factors (using QRISK2® scores) in AATD. There were no such relationships with QRISK2® in AATD. AATD patients with confirmed CVD at four-year follow up had a higher aPWV but not QRISK2® at baseline assessment.ConclusionaPWV measured CVD risk is elevated in AATD. This risk is not captured by QRISK2®. There is a relationship between aPWV, lung disease and proteinase-3 activity. Proteinase-driven breakdown of elastin fibres in large arteries and lungs is a putative mechanism and forms a potential therapeutic target for CVD in AATD.

Cluster randomised controlled trial of specialist-led integrated COPD care (INTEGR COPD)

ObjectiveStudies in hospital settings demonstrate that there is greater guideline adherence when care is delivered by a respiratory specialist, however, this has not been explored in primary care. The aim...

Pulmonary Rehabilitation for Chronic Obstructive Pulmonary Disease Patients with Underlying Alpha-1 Antitrypsin Deficiency: A Systematic Review and Practical Recommendations.

Alpha-1 antitrypsin deficiency (AATD) is an often-overlooked genetic condition that makes individuals susceptible to early onset of chronic obstructive pulmonary disease (COPD). The established benefits of exercise-based pulmonary rehabilitation (PR) for usual COPD patients are unclear for those with underlying AATD, especially given potentially differing muscle adaptations to exercise. This review seeks to compare PR outcomes between AATD and usual COPD patients and to consolidate current knowledge on exercise intervention outcomes for the AATD population. A thorough search of 4 databases (Ovid, Medline, CINAHL, CENTRAL) was conducted based on 3 search concepts: (1) alpha-1 antitrypsin deficiency, (2) pulmonary rehabilitation OR exercise, and (3) muscle morphology. A dual review process and quality assessment were independently implemented throughout all stages of the review. Four studies highlighted modest exercise capacity and quality of life in AATD patients undergoing PR. However, one study reported unique muscle and mitochondrial responses compared to usual COPD patients. Additionally, a moderate exercise session did not alter pro-inflammatory cytokine levels in AATD patients, despite higher levels of tumor necrosis factor-α levels in muscle biopsies compared to usual COPD patients. The current literature base insufficiently addresses the efficacy of PR on AATD, with indications that exercise adaptation may deviate from that of usual COPD patients. Further research is needed to optimize PR, particularly in identifying the most suitable exercise intensity, and delivery setting, and addressing specific educational needs for individuals with AATD.

Re-admission and quality of life among patients with chronic obstructive pulmonary disease after telemedicine video nursing consultation - a randomized study.

Our previous study showed a reduced cumulative length of re-admission stays due to chronic obstructive pulmonary disease (COPD) exacerbations during one year after telemedicine video consultation (TVC). The current study evaluated the effects of TVC on the length of re-admission stays within 12 months follow up post-TVC compared to phone call follow up or COPD usual care in a randomized study. Our secondary aim was to assess the impact of TVC on the frequency of re-admissions within 12 months of follow up. Patient satisfaction, hospital anxiety and depression scale (HADS) and COPD assessment test (CAT) scores were also evaluated. The study was a prospective randomized study of COPD patients who after hospital discharge for acute COPD exacerbations, were randomized to monitoring by TVC at home compared to phone call follow up for two weeks by a specialist nurse at the hospital or usual COPD care. Prospectively, we compared the cumulative durations and frequencies of hospital re-admissions due to COPD exacerbations within 12 months follow up after TVC, phone call follow up or usual COPD care. Among 173 COPD patients followed for 12 months, 99 were re-admitted. The median cumulative length of readmission stays per patient within 12 months post-TVC did not differ from those followed by phone calls or with usual COPD care. The number of patients re-admitted and the number of re-admissions due to COPD exacerbations were also equal in the three groups. Patient satisfaction was high among those followed by TVC and phone calls, and the HADS and CAT scores favorably declined from baseline to post-intervention in patients followed by TVC and phone calls. The study could not demonstrate a beneficial effect of TVC on the cumulative length of re-admission stays or on the number of re-admissions within 12 months following an acute COPD hospital stay, as compared to those followed by phone calls or with usual COPD care. Patient satisfaction was high among those followed by TVC and phone calls, and the declines in HADS and CAT scores seem to be consequences of increased empowerment and competence for good self-care in COPD patients, remaining through the one-year observation period.

Better outcomes for everybody evaluates the effectiveness and cost-effectiveness of a pharmacist-led intervention, delivered by community pharmacists in collaboration with physicians, in improving disease control, compared with usual care, in asthma and COPD patients during and after COVID-19

Abstract Introduction: In 2025, more than 400 million people will have asthma, and chronic obstructive pulmonary disease (COPD) will be the third leading cause of death by 2030. This trial, called better outcomes for everybody, will evaluate the effectiveness and cost-effectiveness of a pharmacist-led intervention delivered by community pharmacists in collaboration with physicians to asthma and COPD patients to improve disease control compared with usual care. Methods: A pragmatic parallel 2-arm randomized controlled trial will be conducted in one Italian region (Sicily). A 2:1 randomization and sample size of 900 adult patients (450 with asthma, 450 with COPD) will be sufficient to detect a difference of 15% between the intervention and control groups using a dichotomized score (controlled versus non-controlled) of the Asthma Control Test (ACT) and the Clinical Chronic Obstructive Pulmonary Disease Questionnaire (CCQ) with a two-tails, 99% power and 5% significance level. A hundred pharmacists will recruit 9 consecutive patients each and administer either ACT or CCQ according to the patients’ disease. Patients will be followed up for 12 months, and the pharmacists will meet their patients every three months. The control group will receive usual care, the intervention a bespoke, structured, and systematic consultation immediately after baseline and 6 months later. The primary outcomes are asthma and COPD control at baseline and 12 months. Secondary outcomes: risk of uncontrolled asthma and COPD, number of active ingredients, pharmaceutical care issues, adherence to medications, minimal clinically important differences in asthma and COPD, and a full health economic evaluation. The analysis will follow an intention-to-treat principle. Generalized estimating equations will be used to test the primary outcomes. Ethics approval was obtained. Discussion: This is the first study conducted in Italy to assess the effectiveness and cost-effectiveness of a pharmacist-led intervention in asthma and COPD patients at the same time. This research could introduce a new model of care that can be adapted to other chronic conditions in primary care settings. The results will be disseminated to service users and their families via media, healthcare professionals via professional training and meetings, and researchers via conferences and publications. Trial registration: ISRCTN, ID: 38734433 Registered on June 15, 2021

Development and Relevance of Hypercapnia in COPD.

Background Identification of patients who may become hypercapnic, or develop acidotic hypercapnic respiratory failure (AHRF), is important in chronic obstructive pulmonary disease (COPD) to avoid hospital admission and select patients for use of home NIV. This study aimed to identify factors associated with presence and development of hypercapnia. Methods 1224 patients, 637 with COPD and 587 with alpha 1 antitrypsin deficiency (AATD), from 4 previously established patient cohorts, were included in cross-sectional analyses of hypercapnia (PaCO2 ≥ 6.5 kPa or 48.8 mmHg), focusing on phenotypic features of COPD and mortality. Longitudinal associations of rising PaCO2 were also assessed. A second cohort of 160 COPD patients underwent sleep studies and 1-year follow-up, analysing in a similar way, incorporating additional information from their sleep studies if appropriate. Results Hypercapnia was 15 times more common in usual COPD than AATD (p < 0.01) after adjustment for baseline differences by regression. Independent predictors of hypercapnia in COPD included FEV1 and current use of oxygen; these variables, together with lack of emphysema, explained 11% of variance in CO2. Increasing PaCO2 also associated with higher risk of death (p=0.03). 44/160 patients exhibited sleep disordered breathing. The sleep study cohort also showed an association of low FEV1 with hypercapnia. Prior hospital admission for AHRF was also clinically significant, being a feature of almost double the number of hypercapnic patients in both test and sleep study COPD cohorts. Conclusion Lower FEV1 and prior AHRF are the main associations of hypercapnia in COPD, which carries a poor prognosis, particularly worsening over time.

Exacerbations of Lung Disease in Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is an important risk factor for development of chronic obstructive pulmonary disease (COPD). Patients with AATD classically develop a different pattern of lung disease from those with usual COPD, decline faster and exhibit a range of differences in pathogenesis, all of which may be relevant to phenotype and/or impact of exacerbations. There are a number of definitions of exacerbation, with the main features being worsening of symptoms over at least 2 days, which may be associated with a change in treatment. In this article we review the literature surrounding exacerbations in AATD, focusing, in particular, on ways in which they may differ from such events in usual COPD, and the potential impact on clinical management.

Immunoglobulin E as a Biomarker for the Overlap of Atopic Asthma and Chronic Obstructive Pulmonary Disease.

Asthma-COPD overlap (ACO) is a common clinical syndrome, yet there is no single objective definition. We hypothesized that immunoglobulin E (IgE) measurements could be used to refine the definition of ACO. In baseline plasma samples from 2870 participants in the COPD Genetic Epidemiology (COPDGene®) study, we measured total IgE levels and specific IgE levels to 6 common allergens. Compared to usual chronic obstructive pulmonary disease (COPD), participants with ACO (based on self-report of asthma) had higher total IgE levels (median 67.0 versus 42.2 IU/ml) and more frequently had at least one positive specific IgE (43.5% versus 24.5%). We previously used a strict definition of ACO in participants with COPD, based on self-report of a doctor's diagnosis of asthma before age 40. This strict ACO definition was refined by the presence of atopy, determined by total IgE > 100 IU/ml or at least one positive specific IgE, as was the broader definition of ACO based on self-reported asthma history. Participants with all 3 ACO definitions were younger (mean age 60.0-61.3 years), were more commonly African American (36.8%-44.2%), had a higher exacerbation frequency (1.0-1.2 in the past year), and had more airway wall thickening on quantitative analysis of chest computed tomography (CT) scans. Among participants with ACO, 37%-46% did not have atopy; these individuals had more emphysema on chest CT scan. Based on associations with exacerbations and CT airway disease, IgE did not clearly improve the clinical definition of ACO. However, IgE measurements could be used to subdivide individuals with atopic and non-atopic ACO, who might have different biologic mechanisms and potential treatments.

A specific proteinase 3 activity footprint in α1-antitrypsin deficiency.

α1-Antitrypsin (α1-AT) deficiency is a risk factor for emphysema due to tissue damage by serine proteases. Neutrophil elastase (NE) has long been considered the enzyme responsible. However, proteinase 3 (PR3) also produces the pathological features of chronic obstructive pulmonary disease (COPD), is present in the same granules in the neutrophil and is inhibited after NE. We developed a specific footprint assay for PR3 activity and assessed its relationship to an NE footprint in α1-AT deficiency.An ELISA was developed for the specific PR3 fibrinogen cleavage site Aα-Val541. Levels were measured in plasma from 239 PiZZ patients, 94 PiSZ patients, 53 nondeficient healthy smokers and 78 individuals with usual COPD. Subjects underwent extensive demographic characterisation including full lung function and lung computed tomography scanning.Aα-Val541 was greater than the NE footprint in all cohorts, consistent with differential activity. Values were highest in the PiZZ α1-AT-deficient patients and correlated with the NE marker Aα-Val360, but were ∼17 times higher than for the NE footprint, consistent with a greater potential contribution to lung damage. Aα-Val541 was related cross-sectionally to the severity of lung disease (forced expiratory volume in 1 s % pred: rs= −0.284; p<0.001) and was sensitive to augmentation therapy, falling from 287.2 to 48.6 nM (p<0.001).An in vivo plasma footprint of PR3 activity is present in greater quantities than an NE footprint in patients with α1-AT deficiency, is sensitive to augmentation therapy and represents a likely biomarker for dose-ranging studies.

Effect of erdosteine on the rate and duration of COPD exacerbations: the RESTORE study.

Oxidative stress contributes to chronic obstructive pulmonary disease (COPD) exacerbations and antioxidants can decrease exacerbation rates, although we lack data about the effect of such drugs on exacerbation duration.The RESTORE (Reducing Exacerbations and Symptoms by Treatment with ORal Erdosteine in COPD) study was a prospective randomised, double-blind, placebo-controlled study, enrolling patients aged 40–80 years with Global Initiative for Chronic Obstructive Lung Disease stage II/III. Patients received erdosteine 300 mg twice daily or placebo added to usual COPD therapy for 12 months. The primary outcome was the number of acute exacerbations during the study.In the pre-specified intention-to-treat population of 445 patients (74% male; mean age 64.8 years, forced expiratory volume in 1 s 51.8% predicted) erdosteine reduced the exacerbation rate by 19.4% (0.91 versus. 1.13 exacerbations·patient−1·year−1 for erdosteine and placebo, respectively; p=0.01), due to an effect on mild events; the reduction in the rate of mild exacerbations was 57.1% (0.23 versus 0.54 exacerbations·patient−1·year−1 for erdosteine and placebo, respectively; p=0.002). No significant difference was observed in the rate of moderate and severe exacerbations (0.68 versus 0.59 exacerbations·patient−1·year−1 for erdosteine and placebo, respectively; p=0.054) despite a trend in favour of the comparison group. Erdosteine decreased the exacerbation duration irrespective of event severity by 24.6% (9.55 versus 12.63 days for erdosteine and placebo, respectively; p=0.023). Erdosteine significantly improved subject and physician subjective severity scores (p=0.022 and p=0.048, respectively), and reduced the use of reliever medication (p<0.001), but did not affect the St George's Respiratory Questionnaire score or the time to first exacerbation.In patients with COPD, erdosteine can reduce both the rate and duration of exacerbations. The percentage of patients with adverse events was similar in both the placebo and erdosteine treatment groups.

Clinical utility of alpha-1 proteinase inhibitor in the management of adult patients with severe alpha-1 antitrypsin deficiency: a review of the current literature.

Alpha-1 antitrypsin (AAT) functions primarily to inhibit neutrophil elastase, and its deficiency predisposes individuals to the development of chronic obstructive pulmonary disease (COPD). The putative protective serum concentration is generally considered to be above a threshold of 11 μM/L, and therapeutic augmentation of AAT above this value is believed to retard the progression of emphysema. Several AAT preparations, all derived from human donor plasma, have been commercialized since approval by the US Food and Drug Administration (FDA) in 1987. Biochemical efficacy has been demonstrated by augmentation of pulmonary antiprotease activity, but demonstration of clinical efficacy in randomized, placebo-controlled trials has been hampered by the practical difficulties of performing conventional studies in a rare disease with a relatively long natural history. Computed tomography has been applied to measure lung density as a more specific and sensitive surrogate outcome measure of emphysema than physiologic indices, such as forced expiratory volume in 1 second, and studies consistently show a therapeutic reduction in the rate of lung density decline. However, convincing evidence of benefit using traditional clinical measures remains elusive. Intravenous administration of AAT at a dose of 60 mg/kg/week is the commonest regime in use and has well-documented safety and tolerability. International and national guidelines on the management of AAT deficiency recommend intravenous augmentation therapy to supplement optimized usual COPD treatment in patients with severe deficiency and evidence of lung function impairment.

Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review.

BackgroundAlpha-1 antitrypsin deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD). The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management.MethodsStandard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354). Eligible studies were those of any treatment used in severe AATD. Randomized controlled trials (RCTs) were the primary focus; however, case series and uncontrolled studies were eligible. All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months). Risk of bias was assessed appropriately according to study methodology.ResultsIn all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation). Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments. Computed tomography (CT) density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide, health status, and exacerbation rates were frequently used as outcomes. Meta-analyses were only possible for RCTs of intravenous augmentation, which slowed progression of emphysema measured by CT density change, 0.79 g/L/year versus placebo (P=0.002), and associated with a small increase in exacerbations 0.29/year (P=0.02). Mortality following lung transplant was comparable between AATD- and non-AATD-related COPD. Surgical reduction of lung volume demonstrated inferior outcomes compared with non-AATD-related emphysema.ConclusionIntravenous augmentation remains the only disease-specific therapy in AATD and there is evidence that this slows decline in emphysema determined by CT density. There is paucity of data around other treatments in AATD. Treatments for usual COPD may not be as efficacious in AATD, and further studies may be required for this disease group.

Free light chains: potential biomarker and predictor of mortality in alpha-1-antitrypsin deficiency and usual COPD.

BackgroundCirculating free light chains (FLCs) can alter neutrophil migration, apoptosis and activation and may be a biomarker of autoimmune disease and adaptive immune system activation. These pathogenic roles could be relevant to lung disease in alpha 1 antitrypsin deficiency (A1ATD) and chronic obstructive pulmonary disease (COPD).MethodsTotal combined (c)FLCs were measured using the FreeLite® assay in 547 patients with A1ATD and 327 patients with usual COPD in the stable state, and assessed for association with clinical phenotype, disease severity, airway bacterial colonisation and mortality. Univariate and multivariate analyses were undertaken.ResultsCirculating cFLCs were static in the stable state when measured on 4 occasions in A1ATD and twice in usual COPD. Levels were inversely related to renal function (A1ATD and COPD p = <0.01), and higher in patients with chronic bronchitis (p = 0.019) and airway bacterial colonisation (p = 0.008). After adjusting for renal function and age the relationship between cFLCs and lung function was weak. Kaplan Meier curves showed that cFLC > normal (43.3 mg/L) significantly associated with mortality in both cohorts (A1ATD p = 0.001, COPD p = 0.013).ConclusionscFLCs may be a promising biomarker for risk stratification in A1ATD and COPD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0348-1) contains supplementary material, which is available to authorized users.

Prevalence and impact of co-morbidity in COPD due to Alpha 1 Antitrypsin deficiency

&lt;p&gt;&lt;strong&gt;Background&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;Alpha 1 antitrypsin deficiency (AATD) is a rare genetic cause of chronic obstructive pulmonary disease (COPD). There are a number of conditions which are recognized to be common as co-morbidities in COPD unrelated to AATD, and a co-morbidity specific prognostic score exists (COTE index). In this manuscript we sought to describe the COPD related, and unrelated, co-morbidities seen in AATD and assess their impact on outcome. The relevant literature is also reviewed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;All PiZZ AATD patients who have COPD from the UK AATD registry were selected, and graded for severity of COPD using the GOLD criteria. Medical notes were reviewed to ascertain co-morbidity, and used to calculate the COTE score. Each co-morbid condition was tested for association with GOLD stage and subsequent death. Multivariate analyses, adjusting for smoking, age and GOLD stage, were used to ascertain independent relationships to death. COTE score was compared between GOLD groups and between survivors and those that died. Selected co-morbid diseases were also assessed using multivariate analyses for their relation to lung function decline.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;The most common co-morbid disease in AATD was bronchiectasis (31.1% of patients). Some common COPD related conditions were seen, such as osteoporosis (11.9%). Liver disease was observed in 5.5% of patients. In univariate analyses the presence of osteoporosis, depression or gastro-oesophageal reflux (GORD) associated with GOLD stage, being more common in group D patients (all p&amp;lt;0.05). No co-morbid disease was associated with death after adjustment for co-variates. COTE scores were generally low and did not differ between survivors and those that died.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;Co-morbid disease is common in AATD, but differs from usual COPD, and has little impact on mortality and lung function decline. The COTE index is not valid for use in AATD.&lt;/p&gt;

Characteristics of Alpha-1 Antitrypsin-Deficient Individuals in the Long-term Oxygen Treatment Trial and Comparison with Other Subjects with Chronic Obstructive Pulmonary Disease.

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. Compare demographic, clinical, baseline oxygenation, and exercise desaturation features in participating AATD subjects with those of other LOTT subjects. 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. 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). 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).

Treatment of Alpha-1 Antitrypsin Deficiency.

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.

Immune activation in α1-antitrypsin-deficiency emphysema. Beyond the protease-antiprotease paradigm.

α1-Antitrypsin (AAT) is a potent protease inhibitor, deficiency of which is associated with the presence of emphysema. An imbalance of elastase and antielastase, along with innate inflammation in the lung, is believed to cause lung destruction in α1-antitrypsin deficiency (AATD). It is now apparent that AAT has important immune-regulatory roles that would be lost in AATD, yet adaptive immune responses in the lung have not been investigated in patients with AATD. To assess the adaptive immune response in severe AATD emphysema and compare it with that present in "usual" chronic obstructive pulmonary disease (COPD). The immune inflammatory response in explanted lungs from 10 subjects with AATD was characterized and quantified, and the results were compared with those of 26 subjects with usual COPD and those of 17 smoking and 11 nonsmoking control subjects with normal lung function. Lymphoid follicles (LFs) in AATD and usual COPD were markedly increased when compared with control groups. Molecular analysis of B lymphocytes in LFs showed predominantly mono/oligoclonality. LF number correlated negatively with FEV1/FVC. B lymphocytes and CD4(+) and CD8(+) T lymphocytes were significantly increased in AATD and usual COPD when compared with control groups. IL-32, an important cytokine in induction of autoimmunity, was markedly up-regulated in AATD and usual COPD. An important adaptive immune inflammation, comprising B, CD4(+), and CD8(+) lymphocytes, and LFs, is a prominent feature in AATD. These results change the paradigm of the mechanism of AATD-induced emphysema from a pure elastase-antielastase imbalance to a much more complex one involving the adaptive immune system, similarly to what occurs in usual COPD.

A self-management programme for COPD: a randomised controlled trial.

Studies of programmes of self-management support for chronic obstructive pulmonary disease (COPD) have been inconclusive. The Self-Management Programme of Activity, Coping and Education (SPACE) FOR COPD is a 6-week self-management intervention for COPD, and this study aimed to evaluate the effectiveness of this intervention in primary care. A single-blind randomised controlled trial recruited people with COPD from primary care and randomised participants to receive usual care or SPACE FOR COPD. Outcome measures were performed at baseline, 6 weeks and 6 months. The primary outcome was symptom burden, measured by the self-reported Chronic Respiratory Questionnaire (CRQ-SR) dyspnoea domain. Secondary outcomes included other domains of the CRQ-SR, shuttle walking tests, disease knowledge, anxiety, depression, self-efficacy, smoking status and healthcare utilisation. 184 people with COPD were recruited and randomised. At 6 weeks, there were significant differences between groups in CRQ-SR dyspnoea, fatigue and emotion scores, exercise performance, anxiety, and disease knowledge. At 6 months, there was no between-group difference in change in CRQ-SR dyspnoea. Exercise performance, anxiety and smoking status were significantly different between groups at 6 months, in favour of the intervention. This brief self-management intervention did not improve dyspnoea over and above usual care at 6 months; however, there were gains in anxiety, exercise performance, and disease knowledge.

Proteinase 3 activity in sputum from subjects with alpha-1-antitrypsin deficiency and COPD

Chronic obstructive pulmonary disease (COPD) is associated with tissue damage believed to result from an imbalance between serine proteinases and their inhibitors. Although the role of neutrophil elastase (NE) has been studied, it is likely that other proteinases play a role. The importance of proteinase 3 (PR3) has not been established, as specific substrates have only recently been available. We studied clinically stable subjects with either alpha-1-antitrypsin (A1AT) deficiency or usual COPD with chronic bronchitis. Sol phase sputum was analysed for PR3 activity and concentration, NE activity and concentration, concentrations of airway inhibitors (A1AT, secretory leukoproteinase inhibitor and elafin) and markers of neutrophilic inflammation. 12 patients were also studied during exacerbations. PR3 activity was present in most sputum samples and greater than NE activity (which was largely undetectable) in both subject groups (A1AT deficiency median PR3 128 nM, interquartile range (IQR) 33-558 nM; NE 0 nM, IQR 0-0 nM; p=0.0043; COPD PR3 22 nM, IQR 0-103 nM; NE 0 nM, IQR 0-0 nM; p=0.015). PR3 activity was greater during exacerbations than in the stable state (p=0.037) and correlated with markers of neutrophilic inflammation. The regular identification of PR3 activity in sputum from stable subjects with A1AT deficiency or usual COPD suggests it may play a greater role in the pathophysiology than previously thought.

Assessment of Pulmonary Neutrophilic Inflammation in Emphysema by Quantitative Positron Emission Tomography

Neutrophilic inflammation is understood to be of pathogenetic importance in chronic obstructive pulmonary disease (COPD) and may be quantified using 18-fluorodeoxyglucose positron emission tomography-computed tomography ((18)FDG PET-CT) as a noninvasive, spatially informative biomarker. To assess the potential usefulness of (18)FDG PET-CT as a surrogate measure of pulmonary neutrophilic inflammation in patients with usual COPD and α(1)-antitrypsin deficiency (AATD). (18)FDG PET-CT imaging was performed in 10 patients with usual COPD, 10 patients with AATD, and 10 healthy control subjects. Pulmonary (18)FDG uptake was estimated by three-dimensional Patlak graphical analysis as an indicator of pulmonary neutrophilic glycolytic activity. Patients with AATD were treated with 12 weekly intravenous infusions of AAT augmentation therapy before repeat imaging. (18)FDG uptake, lung physiology, lung density, and systemic markers of inflammation were compared for all groups at baseline and, in patients with AATD, at baseline and on treatment. (18)FDG uptake in the upper lung of patients with usual COPD was greater compared with the healthy control group (P = 0.009) and correlated with measures of disease severity (FEV(1)% predicted, r = -0.848, P = 0.001; FEV(1)/FVC, r = -0.918, P < 0.001; Kco% predicted, r = -0.624, P = 0.027; 15th percentile point, r = -0.709, P = 0.011). No significant difference was observed between measurements at baseline and on treatment in patients with AATD. Quantitative (18)FDG PET-CT has a potential role as an imaging biomarker in mechanistic and interventional studies in patients with usual COPD. The data support previous evidence of distinct functional characteristics of neutrophils in COPD. Clinical trial registered with https://eudract.ema.europa.eu/index.html (EudraCT 2007-004869-18).