Structural Predictors of Lung Function Decline in Young Smokers with Normal Spirometry.

Rationale: Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. Objectives: We hypothesized that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. Methods: We recruited 431 current smokers (median age, 39 yr; 16 pack-years smoked) and recorded symptoms using the COPD Assessment Test (CAT), spirometry, and quantitative thoracic computed tomography (QCT) scans at study entry. These scan results were compared with those from 67 never-smoking control subjects. Three hundred sixty-eight participants were followed every six months with measurement of postbronchodilator spirometry for a median of 32 months. The rate of FEV1 decline, adjusted for current smoking status, age, and sex, was related to the initial QCT appearances and symptoms, measured using the CAT. Measurements and Main Results: There were no material differences in demography or subjective CT appearances between the young smokers and control subjects, but 55.7% of the former had CAT scores greater than 10, and 24.2% reported chronic bronchitis. QCT assessments of disease probability-defined functional small airway disease, ground-glass opacification, bronchovascular prominence, and ratio of small blood vessel volume to total pulmonary vessel volume were increased compared with control subjects and were all associated with a faster FEV1 decline, as was a higher CAT score. Conclusions: Radiological abnormalities on CT are already established in young smokers with normal lung function and are associated with FEV1 loss independently of the impact of symptoms. Structural abnormalities are present early in the natural history of COPD and are markers of disease progression. Clinical trial registered with www.clinicaltrials.gov (NCT03480347).

Hypoxia Increases the Potential for Neutrophil-mediated Endothelial Damage in Chronic Obstructive Pulmonary Disease.

Rationale: Patients with chronic obstructive pulmonary disease (COPD) experience excess cardiovascular morbidity and mortality, and exacerbations further increase the risk of such events. COPD is associated with persistent blood and airway neutrophilia and systemic and tissue hypoxia. Hypoxia augments neutrophil elastase release, enhancing capacity for tissue injury. Objective: To determine whether hypoxia-driven neutrophil protein secretion contributes to endothelial damage in COPD. Methods: The healthy human neutrophil secretome generated under normoxic or hypoxic conditions was characterized by quantitative mass spectrometry, and the capacity for neutrophil-mediated endothelial damage was assessed. Histotoxic protein concentrations were measured in normoxic versus hypoxic neutrophil supernatants and plasma from patients experiencing COPD exacerbation and healthy control subjects. Measurements and Main Results: Hypoxia promoted PI3Kγ-dependent neutrophil elastase secretion, with greater release seen in neutrophils from patients with COPD. Supernatants from neutrophils incubated under hypoxia caused pulmonary endothelial cell damage, and identical supernatants from COPD neutrophils increased neutrophil adherence to endothelial cells. Proteomics revealed differential neutrophil protein secretion under hypoxia and normoxia, and hypoxia augmented secretion of a subset of histotoxic granule and cytosolic proteins, with significantly greater release seen in COPD neutrophils. The plasma of patients with COPD had higher content of hypoxia-upregulated neutrophil-derived proteins and protease activity, and vascular injury markers. Conclusions: Hypoxia drives a destructive "hypersecretory" neutrophil phenotype conferring enhanced capacity for endothelial injury, with a corresponding signature of neutrophil degranulation and vascular injury identified in plasma of patients with COPD. Thus, hypoxic enhancement of neutrophil degranulation may contribute to increased cardiovascular risk in COPD. These insights may identify new therapeutic opportunities for endothelial damage in COPD.

The prevalence of bronchodilator responsiveness of the small airway (using mid-maximal expiratory flow) in COPD - a retrospective study.

BACKGROUND: Bronchodilator responsiveness (BDR) using FEV1 is often utilised to separate COPD patients from asthmatics, although it can be present in some COPD patients. With the advent of treatments with distal airway deposition, BDR in the small airways (SA) may be of value in the management of COPD. We aimed to identify the prevalence of BDR in the SA, utilizing maximal mid-expiratory flow (MMEF) as a measure of SA. We further evaluated the prevalence of BDR in MMEF with and without BDR in FEV1 and its association with baseline demographics, including conventional airflow obstruction severity and smoking history. METHODS: Lung function data of ever-smoking COPD patients were retrospectively analysed. BDR was evaluated 20 min after administering 2.5 mg of salbutamol via jet nebulizer. Increase in percent change of ≥ 12% and absolute change of ≥ 200 ml was used to define a BDR in FEV1, whereas an increase percent change of MMEF ≥ 30% was used to define a BDR in MMEF. Patients were classified as one of three groups according to BDR levels: group 1 (BDR in MMEF and FEV1), group 2 (BDR in MMEF alone) and group 3 (no BDR in either measure). RESULT: BDR in MMEF was present in 59.2% of the patients. Of note, BDR in MMEF was present in all patients with BDR in FEV1 (group 1) but also in 37.9% of the patients without BDR in FEV1 (group 2). Patients in group 1 were younger than in groups 2 and 3. BMI was higher in group 1 than in group 3. Baseline FEV1% predicted and FVC % predicted were also higher in groups 1 and 2 than in group 3. CONCLUSION: BDR in the SA (evaluated by MMEF) is common in COPD, and it is also feature seen in all patients with BDR in FEV1. Even in the absence of BDR in FEV1, BDR in MMEF is detected in some patients with COPD, potentially identifying a subgroup of patients who may benefit from different treatment strategies.

Relationship between Emphysema Progression at CT and Mortality in Ever-Smokers: Results from the COPDGene and ECLIPSE Cohorts.

Background The relationship between emphysema progression and long-term outcomes is unclear. Purpose To determine the relationship between emphysema progression at CT and mortality among participants with emphysema. Materials and Methods In a secondary analysis of two prospective observational studies, COPDGene (clinicaltrials.gov, NCT00608764) and Evaluation of Chronic Obstructive Pulmonary Disease Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE; clinicaltrials.gov, NCT00292552), emphysema was measured at CT at two points by using the volume-adjusted lung density at the 15th percentile of the lung density histogram (hereafter, lung density perc15) method. The association between emphysema progression rate and all-cause mortality was analyzed by using Cox regression adjusted for ethnicity, sex, baseline age, pack-years, and lung density, baseline and change in smoking status, forced expiratory volume in 1 second, and 6-minute walk distance. In COPDGene, respiratory mortality was analyzed by using the Fine and Gray method. Results A total of 5143 participants (2613 men [51%]; mean age, 60 years ± 9 [standard deviation]) in COPDGene and 1549 participants (973 men [63%]; mean age, 62 years ± 8) in ECLIPSE were evaluated, of which 2097 (40.8%) and 1179 (76.1%) had emphysema, respectively. Baseline imaging was performed between January 2008 and December 2010 for COPDGene and January 2006 and August 2007 for ECLIPSE. Follow-up imaging was performed after 5.5 years ± 0.6 in COPDGene and 3.0 years ± 0.2 in ECLIPSE, and mortality was assessed over the ensuing 5 years in both. For every 1 g/L per year faster rate of decline in lung density perc15, all-cause mortality increased by 8% in COPDGene (hazard ratio [HR], 1.08; 95% CI: 1.01, 1.16; P = .03) and 6% in ECLIPSE (HR, 1.06; 95% CI: 1.00, 1.13; P = .045). In COPDGene, respiratory mortality increased by 22% (HR, 1.22; 95% CI: 1.13, 1.31; P < .001) for the same increase in the rate of change in lung density perc15. Conclusion In ever-smokers with emphysema, emphysema progression at CT was associated with increased all-cause and respiratory mortality. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Lee and Park in this issue.

Relationship between Depression and Anxiety, Health Status and Lung Function in Patients with Alpha-1 Antitrypsin Deficiency.

Alpha-1 Antitrypsin deficiency (AATD) is a genetic condition that can lead to Chronic Obstructive Pulmonary Disease. The burden of psychological disease, its impact and contributing factors in patients with AATD are largely unknown. This study determined the prevalence of depression and anxiety in AATD and its clinical impact. All subjects with PiZZ/PiZnull (n = 635) and PiSZ (n = 111) genotypes within the AATD registry who had sufficient data to calculate pulmonary physiological and health status (HS) decline were grouped as those with or without a diagnosis of depression and/or anxiety. Univariate and multivariate analyses were performed on physiological, demographic and HS parameters. Depression and/or anxiety was present in 16.4% overall in both PiSZ and PiZZ/PiZnull cohorts and was associated with lower baseline pulmonary function and worse HS. In the multivariable analysis of the PiZZ/PiZnull cohort, a greater average decline in FEV1% predicted was observed in those with depression and/or anxiety than those without (-1.53 SD ± 2.26 per year, -0.99 ± 1.79, respectively; p = 0.03) but there was no difference in HS decline (p = 0.33). No differences were seen in the PiSZ cohort. Dyspnoea (mMRC score) was generally worse in those with depression and/or anxiety than those without. Comorbidity burden did not differ between those with or without depression and/or anxiety. Disease severity and progression may be contributing to the prevalence of psychological factors in PiZZ/PiZnull patients. Patients who are declining rapidly should be actively monitored for psychological co-morbidity and treated by cognitive or pharmacological means.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1991904 .

Clinical considerations in individuals with α1-antitrypsin PI*SZ genotype.

α1-Antitrypsin deficiency (AATD), characterised by reduced levels or functionality of α1-antitrypsin (AAT), is a significantly underdiagnosed genetic condition that predisposes individuals to lung and liver disease. Most of the available data on AATD are based on the most common, severe deficiency genotype (PI*ZZ); therefore, treatment and monitoring requirements for individuals with the PI*SZ genotype, which is associated with a less severe AATD, are not as clear. Recent genetic data suggest the PI*SZ genotype may be significantly more prevalent than currently thought, due in part to less frequent identification in the clinic and less frequent reporting in registries. Intravenous AAT therapy, the only specific treatment for patients with AATD, has been shown to slow disease progression in PI*ZZ individuals; however, there is no specific evidence for AAT therapy in PI*SZ individuals, and it remains unclear whether AAT therapy should be considered in these patients. This narrative review evaluates the available data on the PI*SZ genotype, including genetic prevalence, the age of diagnosis and development of respiratory symptoms compared with PI*ZZ individuals, and the impact of factors such as index versus non-index identification and smoking history. In addition, the relevance of the putative 11 µM "protective threshold" for AAT therapy and the risk of liver disease in PI*SZ individuals is explored. The purpose of this review is to identify open research questions in this area, with the aim of optimising the future identification and management of PI*SZ individuals.

Chronic Obstructive Pulmonary Disease Biomarkers and Their Interpretation.

The pathology and impact of chronic obstructive pulmonary disease (COPD) results from an abnormal inflammatory process resulting in tissue damage with ineffective repair in response to toxic inhalants (especially cigarette smoke). Identification of mechanisms provides the opportunity to develop new therapies and a personalized approach to management. The collection of multiple genetic and detailed biochemical data from small and large patient cohorts has led to an explosion of studies investigating biomarkers to achieve these aims. Despite widespread enthusiasm and many statistically significant associations, the interpretation of COPD biomarker results requires thought and leaves many questions unanswered. The present review assesses the importance of these associations, whether they represent cause or effect, reflect disease severity or activity, the complexity of the pathway to the final pathogenic and hence interventional step, and problems with interpreting cross-sectional studies without knowing individual disease trajectories. The complexity of biomarker specificity without sufficient clinical phenotype and endotype information contributes to problems of interpretation. A strategic change is needed to develop useful COPD biomarkers; this includes focusing on endotype biomarkers within specific clinical phenotypes, biomarkers in early COPD, exacerbation subtype biomarkers, and biomarkers to predict or measure drug effects.

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).

Efficacy and safety of inhaled α1-antitrypsin in patients with severe α1-antitrypsin deficiency and frequent exacerbations of COPD.

Patients with inherited α1-antitrypsin (AAT) deficiency (ZZ-AATD) and severe chronic obstructive pulmonary disease (COPD) frequently experience exacerbations. We postulated that inhalation of nebulised AAT would be an effective treatment.We randomly assigned 168 patients to receive twice-daily inhalations of 80 mg AAT solution or placebo for 50 weeks. Patients used an electronic diary to capture exacerbations. The primary endpoint was time from randomisation to the first event-based exacerbation. Secondary endpoints included change in the nature of the exacerbation as defined by the Anthonisen criteria. Safety was also assessed.Time to first moderate or severe exacerbation was a median of 112 days (interquartile range (IQR) 40-211 days) for AAT and 140 days (IQR 72-142 days) for placebo (p=0.0952). The mean yearly rate of all exacerbations was 3.12 in the AAT-treated group and 2.67 in the placebo group (p=0.31). More patients receiving AAT reported treatment-related treatment-emergent adverse events compared to placebo (57.5% versus 46.9%, respectively) and they were more likely to withdraw from the study. After the first year of the study, when modifications to the handling of the nebuliser were introduced, the rate of safety events in the AAT-treated group dropped to that of the placebo group.We conclude that in AATD patients with severe COPD and frequent exacerbations, AAT inhalation for 50 weeks showed no effect on time to first exacerbation but may have changed the pattern of the episodes.

Proteinase 3; a potential target in chronic obstructive pulmonary disease and other chronic inflammatory diseases.

Chronic Obstructive Pulmonary Disease (COPD) is a common, multifactorial lung disease which results in significant impairment of patients' health and a large impact on society and health care burden. It is believed to be the result of prolonged, destructive neutrophilic inflammation which results in progressive damage to lung structures. During this process, large quantities of neutrophil serine proteinases (NSPs) are released which initiate the damage and contribute towards driving a persistent inflammatory state.Neutrophil elastase has long been considered the key NSP involved in the pathophysiology of COPD. However, in recent years, a significant role for Proteinase 3 (PR3) in disease development has emerged, both in COPD and other chronic inflammatory conditions. Therefore, there is a need to investigate the importance of PR3 in disease development and hence its potential as a therapeutic target. Research into PR3 has largely been confined to its role as an autoantigen, but PR3 is involved in triggering inflammatory pathways, disrupting cellular signalling, degrading key structural proteins, and pathogen response.This review summarises what is presently known about PR3, explores its involvement particularly in the development of COPD, and indicates areas requiring further investigation.

Health status decline in α-1 antitrypsin deficiency: a feasible outcome for disease modifying therapies?

BACKGROUND: Trials of disease modifying therapies in Chronic Obstructive Pulmonary Disease (COPD) provide challenges for detecting physiological and patient centred outcomes. The purpose of the current study was to monitor decline in health status in Alpha-1 antitrypsin deficiency (AATD) and determine its' relationship to conventional physiology. METHODS: Patients recruited to the UK-AATD database with a median follow up of 7 years (IQR 5-10) were studied to determine annual change in St George's Respiratory Questionnaire (SGRQ), FEV1, gas transfer and their feasibility of use in future trials. RESULTS: Annual decline in SGRQ had a wide range, was greater for patients with established COPD and correlated with decline in FEV1 (p < 0.0001). Total score decline was greater (p < 0.05) for those with accelerated FEV1 decline (median = 1.07 points/year) compared to those without (median = 0.51). Power calculations indicated effective intervention would not achieve MCID for the SGRQ unless the timeframe was extended for up to 8 years. More than 5000 patients/arm would be required for a statistically significant modest effect over 3 years even in those with rapid FEV1 decline. CONCLUSION: Despite AATD being a rapidly declining form of COPD, deterioration in SGRQ was slow consistent with ageing and the chronic nature of disease progression. Power calculations indicate the numbers needed to detect a difference with disease modifying therapies would be prohibitive especially in this rare cause of COPD. These data have important implications for future study design of disease modifying therapies even in COPD not associated with AATD.

Maximal mid-expiratory flow detects early lung disease in α1-antitrypsin deficiency.

Pathological studies suggest that loss of small airways precedes airflow obstruction and emphysema in chronic obstructive pulmonary disease (COPD). Not all α1-antitrypsin deficiency (AATD) patients develop COPD, and measures of small airways function might be able to detect those at risk.Maximal mid-expiratory flow (MMEF), forced expiratory volume in 1 s (FEV1), ratio of FEV1/forced vital capacity (FVC), health status, presence of emphysema (computed tomography (CT) densitometry) and subsequent decline in FEV1 were assessed in 196 AATD patients.FEV1/FVC, FEV1 % predicted and lung densitometry related to MMEF % pred (r2=0.778, p<0.0001; r2=0.787, p<0.0001; r2=0.594, p<0.0001, respectively) in a curvilinear fashion. Patients could be divided into those with normal FEV1/FVC and MMEF (group 1), normal FEV1/FVC and reduced MMEF (group 2) and those with spirometrically defined COPD (group 3). Patients in group 2 had worse health status than group 1 (median total St George's Respiratory Questionnaire (SGRQ) 23.15 (interquartile range (IQR) 7.09-39.63) versus 9.67 (IQR 1.83-22.35); p=0.006) and had a greater subsequent decline in FEV1 (median change in FEV1 -1.09% pred per year (IQR -1.91-0.04% pred per year) versus -0.04% pred per year (IQR -0.67-0.03% pred per year); p=0.007).A reduction in MMEF is an early feature of lung disease in AATD and is associated with impaired health status and a faster decline in FEV1.

European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency.

α1-antitrypsin deficiency (AATD) is the most common hereditary disorder in adults. It is associated with an increased risk of developing pulmonary emphysema and liver disease. The pulmonary emphysema in AATD is strongly linked to smoking, but even a proportion of never-smokers develop progressive lung disease. A large proportion of individuals affected remain undiagnosed and therefore without access to appropriate care and treatment.The most recent international statement on AATD was published by the American Thoracic Society and the European Respiratory Society in 2003. Since then there has been a continuous development of novel, more accurate and less expensive genetic diagnostic methods. Furthermore, new outcome parameters have been developed and validated for use in clinical trials and a new series of observational and randomised clinical trials have provided more evidence concerning the efficacy and safety of augmentation therapy, the only specific treatment available for the pulmonary disease associated with AATD.As AATD is a rare disease, it is crucial to organise national and international registries and collect information prospectively about the natural history of the disease. Management of AATD patients must be supervised by national or regional expert centres and inequalities in access to therapies across Europe should be addressed.

Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence.

Immunosenescence is the functional deterioration of the immune system during natural aging. Despite increased susceptibility to bacterial infections in older adults, age-associated changes to neutrophil responses are only partially understood, and neutrophil migration has not been characterized in detail. Here we describe reduced chemotaxis but preserved chemokinesis toward a range of inflammatory stimuli in migrating neutrophils isolated from healthy older subjects. Cross-sectional data indicate that migratory behavior changes in the sixth decade of life. Crucially, aberrant migration may increase "bystander" tissue damage and heighten inflammation as a result of excess proteinase release during inaccurate chemotaxis, as well as reducing pathogen clearance. We show evidence of increased neutrophil proteinase activity in older adults, namely, raised levels of neutrophil proteinase substrate-derived peptides and evidence of primary granule release, associated with increased systemic inflammation. Inaccurate migration was causally associated with increased constitutive phosphoinositide 3-kinase (PI3K) signaling; untreated neutrophils from old donors demonstrated significant PI3K activation compared with cells from young donors. PI3K-blocking strategies, specifically inhibition of PI3Kγ or PI3Kδ, restored neutrophil migratory accuracy, whereas SHIP1 inhibition worsened migratory flaws. Targeting PI3K signaling may therefore offer a new strategy in improving neutrophil functions during infections and reduce inappropriate inflammation in older patients.

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

BACKGROUND: Circulating 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). METHODS: Total 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. RESULTS: Circulating 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). CONCLUSIONS: cFLCs may be a promising biomarker for risk stratification in A1ATD and COPD.

An Official American Thoracic Society/European Respiratory Society Statement: Research questions in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. METHODS: Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified. RESULTS: Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. CONCLUSIONS: Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.