Antitrypsin deficiency: still more to learn about the lung after 60†years.

The past 60 years have seen multiple publications related to lung disease in α1-antitrypsin deficiency largely reflecting the pathophysiology, biochemical effect and outcomes of augmentation therapy. However, the complexity of disease phenotype and the impact of the natural history presents problems of patient management, study design and hence interpretation of outcome. Although many national and some international registries exist, the lack of consistent in-depth assessment and importantly, the impact of augmentation therapy likely influences our perception of the true natural history. Development of new therapeutic strategies, and even assessment of the role and efficacy of augmentation, remain a challenge as powering such studies for conventional COPD outcomes is impractical due to relative rarity of the genetic condition and the presence of clinical phenotypic variation. The current review approaches these issues, discusses the nature and complexity of assessing patient variability, and provides guidance on further studies required to address them.

A novel in vitro cell model of the proteinase/antiproteinase balance observed in alpha-1 antitrypsin deficiency.

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting from mutations in the alpha-1 antitrypsin (AAT) protein, a major systemic antiproteinase, resulting in reduced/no release of AAT, disrupting the proteinase/antiproteinase balance. A sustained imbalance can cause structural changes to the lung parenchyma, leading to emphysema. Predicting and assessing human responses to potential therapeutic candidates from preclinical animal studies have been challenging. Our aims were to develop a more physiologically relevant in vitro model of the proteinase/antiproteinase balance and assess whether the data generated could better predict the efficacy of pharmacological candidates to inform decisions on clinical trials, together with expected biomarker responses. Methods: We developed an in vitro model assessing the proteinase/antiproteinase balance by the changes in the fibrinogen cleavage products of neutrophil elastase (NE) and proteinase 3 (PR3). This allowed the assessment of physiological and pharmaceutical neutrophil serine proteinase (NSP) inhibitors to determine the putative threshold at which the maximal effect is achieved. Results: AAT significantly reduced NE and PR3 activity footprints, with the maximal reduction achieved at concentrations above 10 µM. The inhibitor MPH966 alone also significantly reduced NE footprint generation in a concentration-dependent manner, leveling out above 100 nM but had no effect on the PR3 footprint. At levels of AAT consistent with AATD, MPH966 had an additive effect, reducing the NE activity footprint more than either inhibitor alone. Conclusion: Our results support an inhibitor threshold above which the activity footprint generation appears resistant to increasing dosage. Our model can support the testing of inhibitors, confirming activity biomarkers as indicators of likely pharmaceutical efficacy, the assessment of NSP activity in the pathophysiology of emphysema, and the likely function of biological or pharmacological inhibitors in disease management.

Characteristics of alpha-1 antitrypsin deficiency related lung disease exacerbations using a daily symptom diary and urinary biomarkers.

BACKGROUND: Pulmonary exacerbations in alpha-1 antitrypsin deficiency (AATD) related lung disease are a significant contributor to disease burden, as with usual COPD. Separating the early stages of an exacerbation from the day-to-day variation in stable COPD is central to the concerns of both clinicians and patients and has been identified as a research priority by NIHR. Clinical tools that distinguish baseline symptoms from those of an exacerbation could allow early and appropriate treatment of AECOPD to reduce the impact and potentially may slow disease progression thereby improving survival and quality of life. Candidate tools include symptom diaries and biomarkers of infection and acute inflammation. Urinary biomarkers of AECOPD have yet to be explored in AATD related COPD. METHODS: 55 patients with AATD related lung disease with a history of 2 or more AECOPD in the preceding year were prospectively followed for 18 months. Each patient recorded symptom scores daily via an electronic symptom diary (eDiary) based on Bronkotest. Urinary biomarkers for AAT, NE, CRP, TIMP1 and desmosine were measured weekly using a home urinary lateral flow device. During self-reported AECOPD patients were asked to perform urine analysis on the first 7 consecutive days. RESULTS: Type I Anthonisen exacerbations and episodes occurring in autumn/winter lasted longer than Type II/III exacerbations and spring/summer episodes respectively. Median urinary CRP concentration across all study participants increased during Type I AECOPD. eDiary adherence was 68% over a median of 17.8 months (IQR 15.7 to 18.5). CONCLUSIONS: Use of an eDiary and urinary biomarkers to detect and characterise AECOPD remotely in AATD related lung disease is feasible over a prolonged period and paves the way for precision detection of exacerbations.

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).

Small airways dysfunction: The importance of utilising Z-scores to define MMEF abnormalities in clinical practice.

Background: The small airways comprise the largest cross-sectional area of the lungs, however, assessing and reporting abnormalities for this region of the bronchial tree has been practically and scientifically uncertain. Methods: Using routinely collected spirometry data for patients with either asthma or COPD, the accuracy of % predicted values for defining small airways dysfunction was assessed. A z-score of ≤ -1.645 of the maximal-mid expiratory flow (MMEF) was used as the gold standard for defining abnormality in the small airways. Results: Records of 3396 patients were included in the analysis. The false positive (FP) rates were 24.6 %, 16.1 %, 11.5 %, or 7.9 % when the % predicted value of 80 %, 70 %, 65 %, or 60 % were used, respectively. Sex, age, and BMI were associated with FP rates. Males were more likely to be categorised as FP with odds ratio (OR) between 1.10 and 1.49 across % predicted groups. Age was associated with FP rates with an OR between 1.01 and 1.08. The BMI was also associated with FP rates with an OR of 1.03 across all % predicted groups. Assessing the association of age groups with FP rate showed that those above 60 years old were more likely to be categorised as FP with an OR between 1.23 and 73.2 compared to those less than 30 years old. Conclusion: When assessing the small airways in clinical practice or for scientific purposes, the % predicted values overestimate the actual impairment leading to FP interpretation. Utilising z-score values are recommended to assess the small airways using the spirometric index, MMEF.

The prevalence of bronchiectasis in patients with alpha-1 antitrypsin deficiency: initial report of EARCO.

BACKGROUND: Although bronchiectasis has been recognised as a feature of some patients with Alpha1-Antitrypsin deficiency the prevalence and characteristics are not widely known. We wished to determine the prevalence of bronchiectasis and patient characteristics. The first cohort of patients recruited to the EARCO (European Alpha1 Research Collaboration) International Registry data base by the end of 2021 was analysed for radiological evidence of both emphysema and bronchiectasis as well as baseline demographic features. RESULTS: Of the first 505 patients with the PiZZ genotype entered into the data base 418 (82.8%) had a reported CT scan. There were 77 (18.4%) with a normal scan and 38 (9.1%) with bronchiectasis alone. These 2 groups were predominantly female never smokers and had lung function in the normal range. The remaining 303 (72.5%) ZZ patients all had emphysema on the scan and 113 (27%) had additional evidence of bronchiectasis. CONCLUSIONS: The data indicates the bronchiectasis alone is a feature of 9.1% of patients with the PiZZ genotype of Alpha1-antitrypsin deficiency but although emphysema is the dominant lung pathology bronchiectasis is also present in 27% of emphysema cases and may require a different treatment strategy.

Air pollution and COPD: GOLD 2023 committee report.

Exposure to air pollution is a major contributor to the pathogenesis of COPD worldwide. Indeed, most recent estimates suggest that 50% of the total attributable risk of COPD may be related to air pollution. In response, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Scientific Committee performed a comprehensive review on this topic, qualitatively synthesised the evidence to date and proffered recommendations to mitigate the risk. The review found that both gaseous and particulate components of air pollution are likely contributors to COPD. There are no absolutely safe levels of ambient air pollution and the relationship between air pollution levels and respiratory events is supra-linear. Wildfires and extreme weather events such as heat waves, which are becoming more common owing to climate change, are major threats to COPD patients and acutely increase their risk of morbidity and mortality. Exposure to air pollution also impairs lung growth in children and as such may lead to developmental COPD. GOLD recommends strong public health policies around the world to reduce ambient air pollution and for implementation of public warning systems and advisories, including where possible the use of personalised apps, to alert patients when ambient air pollution levels exceed acceptable minimal thresholds. When household particulate content exceeds acceptable thresholds, patients should consider using air cleaners and filters where feasible. Air pollution is a major health threat to patients living with COPD and actions are urgently required to reduce the morbidity and mortality related to poor air quality around the world.

Quality of Life and Mortality Outcomes for Augmentation Naïve and Augmented Patients with Severe Alpha-1 Antitrypsin Deficiency.

Background: Intravenous alpha-1 antitrypsin (AAT) augmentation therapy is the only specific treatment available for alpha-1 antitrypsin deficiency (AATD)-related lung disease. It is widely used worldwide but remains unavailable to patients with AATD in the United Kingdom. While randomized trials of augmentation therapy have demonstrated biochemical efficacy and lung tissue preservation using computed tomography (CT) densitometry, these studies were not adequately powered to demonstrate effectiveness in well-accepted clinical endpoints such as quality of life (QOL) or survival. We used large, prospectively followed AATD patient populations in the United States and United Kingdom to explore these important clinical endpoints. Methods: Our inclusion criterion was adults with severe AATD and associated lung disease. The treatment group was U.S. AATD patients receiving augmentation therapy for lung disease. The control group was augmentation therapy naïve AATD patients. Multivariable regression and survival analyses were used to assess QOL and mortality outcomes respectively. Results: Mean annual deterioration of the St George's Respiratory Questionnaire total score was 1.43 points greater/year in the control group compared to those receiving augmentation therapy (95% confidence interval [CI] 0.47 to 2.39, p=0.003). At 7 years, median survival was 82.7% (95% CI 75.3 to 90.7) for the control group versus 87.8% (95% CI 82.8 to 93.2) in the augmentation group, p=0.66. There was significant heterogeneity between cohorts. Conclusions: A comparison of 2 highly characterized AATD cohorts was not able to reliably determine if AAT augmentation therapy improves QOL or mortality in patients with severe AATD-related lung disease. Alternative surrogate biomarkers of disease progression, such as CT lung density, may be a more pragmatic option.

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.

Small airway function measured using forced expiratory flow between 25% and 75% of vital capacity and its relationship to airflow limitation in symptomatic ever-smokers: a cross-sectional study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is diagnosed and its severity graded by traditional spirometric parameters (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and FEV1, respectively) but these parameters are considered insensitive for identifying early pathology. Measures of small airway function, including forced expiratory flow between 25% and 75% of vital capacity (FEF25-75), may be more valuable in the earliest phases of COPD. This study aimed to determine the prevalence of low FEF25-75 in ever-smokers with and without airflow limitation (AL) and to determine whether FEF25-75 relates to AL severity. METHOD: A retrospective analysis of lung function data of 1458 ever-smokers suspected clinically of having COPD. Low FEF25-75 was defined by z-score<-0.8345 and AL was defined by FEV1/FVC z-scores<-1.645. The severity of AL was evaluated using FEV1 z-scores. Participants were placed into three groups: normal FEF25-75/ no AL (normal FEF25-75/AL-); low FEF25-75/ no AL (low FEF25-75/AL-) and low FEF25-75/ AL (low FEF25-75/AL+). RESULTS: Low FEF25-75 was present in 99.9% of patients with AL, and 50% of those without AL. Patients in the low FEF25-75/AL- group had lower spirometric measures (including FEV1 FEF25-75/FVC and FEV3/FVC) than those in the normal FEF25-75/AL- group. FEF25-75 decreased with AL severity. A logistic regression model demonstrated that in the absence of AL, the presence of low FEF25-75 was associated with lower FEV1 and FEV1/FVC even when smoking history was accounted for. CONCLUSIONS: Low FEF25-75 is a physiological trait in patients with conventional spirometric AL and likely reflects early evidence of impairment in the small airways when spirometry is within the 'normal range'. FEF25-75 likely identifies a group of patients with early evidence of pathological lung damage who warrant careful monitoring and reinforced early intervention to abrogate further lung injury.

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.

Small Airways Response to Bronchodilators in Adults with Asthma or COPD: A Systematic Review.

BACKGROUND: Bronchodilator responsiveness (BDR) is commonly used in the diagnosis of lung disease. Although small airways dysfunction is a feature of asthma and COPD, physiological tests of small airways are not included in guidelines for BDR testing. This systematic review assessed the current evidence of BDR using small airways function in asthma and COPD. METHODS: The systematic review used standard methodology with the protocol prospectively registered on PROSPERO (CRD42020164140). Electronic medical databases (EMBASE and Medline) were searched using related keywords. Abstracts and full texts were screened independently by two reviewers. Studies that reported the change of physiological small airways function and FEV1 were included in the review. The revised Cochrane risk of bias tool for RCT and NIH quality assessment tool for cohort and cross-sectional studies were used to evaluate the studies. RESULTS: A total of 934 articles were identified, with 12 meeting the inclusion criteria. Ten studies included asthma patients, 1 study included COPD patients and 1 study included both asthma and COPD. A total of 1104 participants were included, of whom 941 were asthmatic, 64 had COPD and 109 were healthy controls. Studies were heterogeneous in design including the device, dose and time intervals for BDR assessment. A small airway BDR was seen for most tests in asthma and COPD, including oscillometry (R5-20, reactance (X5), area of reactance (AX) and resonant frequency (Fres)) and Maximal Mid Expiratory Flow. CONCLUSION: There is a measurable BDR in the small airways. However, with no consensus on how to assess BDR, studies were heterogeneous. Further research is needed to inform how BDR should be assessed, its clinical impact and place in routine clinical practice.

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 .

Long-term effect of α1-antitrypsin augmentation therapy on the decline of FEV1 in deficient patients: an analysis of the AIR database.

BACKGROUND: Patients with ZZ (Glu342Lys) α-1-antitrypsin deficiency (ZZ-AATD) who received augmentation therapy with α-1-antitrypsin (AAT) in randomised controlled trials over 2-3 years failed to show a significant reduction of the annual decline of forced expiratory volume in 1 s (FEV1). METHODS: To compare the trajectory of FEV1 change during 4 or more years in ZZ-AATD patients with emphysema receiving or not receiving intravenous augmentation therapy, a retrospective analysis of FEV1 values entered in the Alpha-1 International Registry (AIR) of ZZ-AATD patients from five different European countries (Germany, UK, Spain, Italy and the Netherlands) was performed. The post-bronchodilator FEV1 % predicted values for baseline and follow-up over time from patients were analysed using linear mixed effects models. RESULTS: Data of 374 patients were analysed: 246 untreated and 128 treated with intravenous AAT augmentation therapy. The mean±sd follow-up duration of the untreated group was 8.60±3.34 years and 8.59±2.62 years for the treated group. The mixed effects model analysis showed a mean FEV1 decline of -0.931% predicted per year (95% CI -1.144 to -0.718) in the untreated group and a decline of -1.016% predicted per year (95% CI -1.319 to -0.7145) in the treated group. The likelihood ratio test showed no difference between the two groups (p=0.71). CONCLUSION: In our study population, we could not detect a significant difference in the annual decline of FEV1 by AAT augmentation treatment over a mean period of 8.6 years. Other approaches are needed to validate any benefit of augmentation therapy.

Catching "Early" COPD - The Diagnostic Conundrum.

Chronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality worldwide. Despite this, there has been little progress so far in terms of disease-modifying therapies over the last few decades and this is in part due to poor understanding of the definition and mechanisms surrounding early disease before it becomes established and increasingly complex. In this review, the nuances and difficulty in defining early disease in COPD are discussed. There are clear benefits in identifying patients early; however, usually diagnosis is made in the presence of significant lung damage. We consider what can be learned of early disease from COPD studies and highlight the lack of inclusion of young smokers (who may be at risk of COPD) or those with mild disease. We discuss promising clinical measures that are being used in an effort to detect early disease. These include symptom assessment, lung physiology measures and computed tomography (CT) imaging modalities. There is emerging evidence for the role of neutrophils and their proteinases in early COPD. This may form an important biomarker to investigate the pathophysiological processes of early COPD. Given the importance of the early disease, it is recommended that future COPD studies focus on capturing the earliest manifestations of disease, to understand the initiating mechanisms and to identify novel treatment targets.