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ObjectiveAlpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the ‘Pi*Z’ variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous ‘Pi*Z’ carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common ‘Pi*S’ variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD.DesignBaseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption.ResultsAmong UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8–53.7)) and primary liver cancer (aOR=44.5 (10.8–183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2–2.2)) and cholelithiasis (aOR=1.3 (1.2–1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1–8.2)) and primary liver cancer (aOR=6.6 (1.6–26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis.ConclusionOur study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

Due to the uncertain disease trajectory and variable rate of progression in chronic obstructive pulmonary disease (COPD), health care professionals (HCPs) are challenged in explaining what the future may hold for patients compared to those with lung cancer (LC). Support and communication of timely information can significantly improve health outcomes.This study sought to identify factors that impact communication and support and recommend ways to improve patients' understanding of living with life-threatening illness.Semi-structured interviews with patients with LC (n = 22) and advanced COPD (n = 18), their informal carers (21 LC and 18 COPD) and HCPs (n = 51). Patients were recruited from primary and secondary care in the East of England, UK, during 2010-12.Directness and clarity characterized communication in LC, whereas uncertainty and limited explanations predominated in COPD. Discussions on how the disease might impact on decisions and preferences to be made in the future were less common in COPD. Information for LC patients was mainly from hospital clinicians and any information for COPD patients mainly from primary care clinicians.The experience of COPD patients could be improved by professionals soon after diagnosis explaining to them the typical pattern of decline in COPD, highlighting the inherent uncertainties about when exacerbations and death may occur. This conversation should lead to planning for the different challenges that the patient and informal carer recognize as most important to them. This contrasts with the 'breaking bad news' conversation that oncologists are highly trained to deliver.People living with lung cancer (LC) or chronic obstructive pulmonary disease (COPD) have poor health-related quality of life. However, more people with LC receive holistic palliative care (which involves supportive advance care planning) than those with COPD. We interviewed patients with LC or COPD, their informal carers (family/friends who support them) and health care professionals (HCPs) about their experiences and our findings confirmed this: HCPs said the uncertainty of COPD prognosis made starting advance care planning conversations challenging. The level of uncertainty and unpredictability is very different in LC and COPD: the cancer diagnosis is made at a single point in time with mortality immediately on the agenda, while COPD is a chronic condition that develops over many years. We urge clinicians to share this uncertainty with patients and to try to explain and communicate it sooner than later. These conversations should also continue as a recognized part of ongoing care so that COPD patients can benefit from understanding the uncertainties they are dealing and living with. LC and COPD should be approached differently to meet patients’ condition-specific needs in order that the existing disparity in holistic care can be remedied.

The seminal observation of severe deficiency of alpha-1-antitrypsin (AAT) with premature emphysema over 50 years ago led to the elastase–antielastase hypothesis of lung disease. Subsequent research identified alpha-1-antitrypsin deficiency (AATD) as an inherited metabolic genetic condition caused by mutations on the SERPINA1 gene, resulting in a reduction in the serum concentration of AAT.1 The role of AAT is to act as an inhibitor to the enzyme neutrophil elastase, and it is crucial in the homeostasis of elastase–antielastase activity, with an imbalance in this activity causing lung disease via a cycle of inflammation and proteolytic damage leading to premature emphysema, disability and death. There are over 100 mutations of SERPINA1 described in the literature, some of which are associated with AATD. The normal genotype is designated PiMM; the most common genotype resulting in severe deficiency is designated PiZZ. AATD is an autosomal codominant condition so heterozygosity can also create in genotypes resulting in mild and intermediate deficiency, such as PiMZ and PiSZ. The prevalence of AATD worldwide is estimated between 0.02% and 0.05%. Normal AAT serum concentration would be in the range 20–53 µmol/L, while deficient genotypes express varying levels, from 55% for PiMZ to 40% for PiSZ and

Funder: Foundation for the National Institutes of Health; FundRef: http://dx.doi.org/10.13039/100000009, OBJECTIVES: To establish a database network for the study of alpha-1 antitrypsin deficiency (AATD) and compare the results to CT lung density as the most direct measure of emphysema. DESIGN: A central electronic database was established to permit the upload of anonymised patient data from remote sites. Prospectively collected CT data were recorded onto disc, anonymised, analysed at the coordinating centre and compared with the clinical features of the disease. SETTING: Tertiary referral centres with expertise in the management of AATD focused on academic Biomedical Research Units and Wellcome Clinical Research Facilities. PARTICIPANTS: Data were collected from 187 patients over 1 year from eight UK academic sites. This included patient demographics, postbronchodilator physiology, health status and CT. Analysis was undertaken at the coordinating centre in Birmingham. RESULTS: Patient recruitment in the 12 months reached 94% of target (set at 200) covering the whole spectrum of the disease from those with normal lung function to very severe chronic obstructive lung disease. CT scan suitable for analysis was available from 147 (79%) of the patients. CT density, analysed as the threshold for the lowest 15% of lung voxels, showed statistically significant relationships with the objective physiological parameters of lung function as determined by spirometric Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity staging (p

Rationale and objectives Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that leads to an increased risk of emphysema and liver disease. Despite extensive investigation, there remain unanswered questions concerning the natural history, pathophysiology, genetics and the prognosis of the lung disease in association with AATD. The European Alpha-1 Clinical Research Collaboration (EARCO) is designed to bring together researchers from European countries and to create a standardised database for the follow-up of patients with AATD. Study design and population The EARCO Registry is a non-interventional, multicentre, pan-European, longitudinal observational cohort study enrolling patients with AATD. Data will be collected prospectively without interference/modification of patient's management by the study team. The major inclusion criterion is diagnosed severe AATD, defined by an AAT serum level, The EARCO Registry is a non-interventional, multicentre, pan-European, longitudinal observational cohort study enrolling patients with AATD to elucidate the natural history, pathophysiology, genetics and prognosis of this condition http://bit.ly/369ScCc

Chronic obstructive pulmonary disease (COPD) is a complex disease and the management is focused on improving breathlessness, quality of life and healthcare utilisation. Our understanding of COPD phenotypes has improved in recent years and there is an increased drive towards delivering phenotype-based therapies. Lung volume reduction can offer the prospect of life changing benefit in breathlessness and quality of life in a select group of patients with severe emphysema already receiving maximum medical treatment. In spite of the available evidence, very few procedures are being performed relative to the disease burden and prevalence of suitable individuals. Currently the major barriers to patient accessibility are lack in standardised multidisciplinary severe COPD services with easy access to lung volume reduction procedures, as well as poorly informed perceptions of healthcare professionals. There is a recognised need to improve such services in many healthcare systems. We share our experiences with setting up and running a successful regional multidisciplinary severe COPD hyperinflation service.

We describe two cases of patients with emphysema who, in the lead up to hyperinflation intervention, developed pneumonia with significant physiological, anatomical, functional and quality of life improvement observed following. This directly goes against the natural history of both disease processes, demonstrating the benefit resulting from infective autobullectomy. Keywords: COPD, Autobullectomy, Lung volume reduction

Ella Mi,1 Emma Mi,1 Gail Ewing,2 Ravi Mahadeva,3 A Carole Gardener,4 Hanne Holt Butcher,4 Sara Booth,5 Morag Farquhar6 On behalf of the Living with Breathlessness Study Team 1School of Clinical Medicine, 2Centre for Family Research, University of Cambridge, 3Department of Respiratory Medicine, Cambridge University Hospitals NHS Foundation Trust, 4Department of Public Health and Primary Care, Institute of Public Health, 5Department of Oncology, University of Cambridge, Cambridge, 6School of Health Sciences, University of East Anglia, Norwich, UK Objective: Anxiety and depression are highly prevalent in patients with COPD and their informal carers, and associated with numerous risk factors. However, few studies have investigated these in primary care or the link between patient and carer anxiety and depression. We aimed to determine this association and factors associated with anxiety and depression in patients, carers, and both(dyads), in a population-based sample.Materials and methods: This was a prospective, cross-sectional study of 119 advanced COPD patients and their carers. Patient and carer scores ≥8 on the Hospital Anxiety and Depression Scale defined symptoms of anxiety and depression, χ2 tests determined associations between patient and carer symptoms of anxiety/depression, and χ2 and independent t-tests for normally distributed variables (otherwise Mann–Whitney U tests) were used to identify other variables significantly associated with these symptoms in the patient or carer. Patient–carer dyads were categorized into four groups relating to the presence of anxious/depressive symptoms in: both patient and carer, patient only, carer only, and neither. Factors associated with dyad symptoms of anxiety/depression were determined with χ2 tests and one-way analysis of variance for normally distributed variables (otherwise Kruskal–Wallis tests).Results: Prevalence of symptoms of anxiety and depression was 46.4% (n=52) and 42.9% (n=48) in patients, and 46% (n=52) and 23% (n=26) in carers, respectively. Patient and carer symptoms of anxiety/depression were significantly associated. Anxious and depressive symptoms in the patient were also significantly associated with more physical comorbidities, more exacerbations, greater dyspnea, greater fatigue, poor mastery, and depressive symptoms with younger age. Symptoms of carer anxiety were significantly associated with being female and separated/divorced/widowed, and depressive symptoms with younger age, higher educational level, and more physical comorbidities, and symptoms of carer anxiety and depression with more unmet support needs, greater subjective caring burden, and poor patient mastery. Dyad symptoms of anxiety/depression were significantly associated with greater patient fatigue.Conclusion: Symptoms of anxiety and depression in COPD patients and carers are significantly associated. Given their high prevalence, considerable impact on mortality, impact on quality of life and health care use, and associations with each other, screening for and addressing patient and carer anxiety and depression in advanced COPD is recommended. Keywords: COPD, anxiety, depression, informal carers, patient–carer dyad

Background: The absence of appropriately sensitive or specific real-time respiratory metrics which are physiologically representative of lung function in normal tidal breathing has, until now, prevented the development of intelligent personalised devices which would facilitate early diagnosis of respiratory deterioration in chronic respiratory disorders such as COPD. Aim: To characterise the temporal progression of COPD with metrics derived from point-of-care capnometry in a population of COPD patients and healthy controls. Methods: 30 patients and 7 healthy controls used new generation LED-based personal capnometers three times daily for up to six weeks. Temporal parameters characterising the changing exhaled CO2 waveforms (angles, tangents, timepoints, ETCO2 values) were extracted by automated mathematical shape analysis. Results: A range of mathematical indices derived from analysis of changing capnometry signatures have allowed categorisation of our COPD cohort into those with (1) minimally changing, (2) increasing and (3) decreasing ETCO2 values (figure) which requires further clinical correlation. Alpha angles clearly distinguish COPD patients (126°-162°) from healthy controls (109-123°). Conclusions: Novel respiratory indices derived from changing capnometry waveform shapes can potentially facilitate temporal disease monitoring and ultimately optimised management of COPD.

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, This novel assay provides evidence of proteinase 3 activity in α1-antitrypsin deficiency, suggesting it may play a significant role in lung tissue damage and act as a specific biomarker for augmentation therapy http://bit.ly/32dnx66

There is a need for straightforward, novel diagnostic and monitoring technologies to enable the early diagnosis of COPD and its differentiation from other respiratory diseases, to establish the cause of acute exacerbations and to monitor disease progression. We sought to establish whether technologies already in development could potentially address these needs. A systematic horizon scanning review was undertaken to identify technologies in development from a wide range of commercial and non-commercial sources. Technologies were restricted to those likely to be available within 18 months, and then evaluated for degree of innovation, potential for impact, acceptability to users and likelihood of adoption by clinicians and patients with COPD. Eighty technologies were identified, of which 25 were considered particularly promising. Biomarker tests, particularly those using sputum or saliva samples and/or available at the point of care, were positively evaluated, with many offering novel approaches to early diagnosis and to determining the cause for acute exacerbations. Several wrist-worn devices and smartphone-based spirometers offering the facility for self-monitoring and early detection of exacerbations were also considered promising. The most promising identified technologies have the potential to improve COPD care and patient outcomes. Further research and evaluation activities should be focused on these technologies.

IntroductionThe purpose of the quality standards document is to provide healthcare professionals, commissioners, service providers and patients with a guide to standards of care that should be met for the provision of acute non-invasive ventilation in adults together with measurable markers of good practice.MethodsDevelopment of British Thoracic Society (BTS) Quality Standards follows the BTS process of quality standard production based on the National Institute for Health and Care Excellence process manual for the development of quality standards.Results6 quality statements have been developed, each describing a standard of care for the provision of acute non-invasive ventilation in the UK, together with measurable markers of good practice.ConclusionBTS Quality Standards for acute non-invasive ventilation in adults form a key part of the range of supporting materials that the Society produces to assist in the dissemination and implementation of guideline’s recommendations.

Emma Mi,1 Ella Mi,1 Gail Ewing,2 Patrick White,3 Ravi Mahadeva,4 A Carole Gardener,5 Morag Farquhar6 On behalf of the Living with Breathlessness Study Team 1School of Clinical Medicine, 2Centre for Family Research, University of Cambridge, Cambridge, 3Primary Care and Public Health Sciences, King’s College London, London, 4Department of Respiratory Medicine, Cambridge NIHR BRC, Addenbrookes Hospital, 5Department of Public Health and Primary Care, University of Cambridge, Cambridge, 6School of Health Sciences, University of East Anglia, Norwich, UK Objective: Accurate informal carer assessment of patient symptoms is likely to be valuable for decision making in managing the high symptom burden of COPD in the home setting. Few studies have investigated agreement between patients and carers in COPD. We aimed to assess agreement between patients and carers on symptoms, and factors associated with disagreement in a population-based sample of patients with advanced COPD. Patients and methods: This was a prospective, cross-sectional analysis of data from 119 advanced COPD patients and their carers. Patients and carers separately rated symptoms on a 4-point scale. Wilcoxon signed-rank tests and weighted Cohen’s kappa determined differences in patient and carer scores and patient–carer agreement, respectively. We identified characteristics associated with incongruence using Spearman’s rank correlation and Mann–Whitney U tests. Results: There were no significant differences between group-level patient and carer scores for any symptom. Patient–carer individual-level agreement was moderate for constipation (k=0.423), just below moderate for diarrhea (k=0.393) and fair for depression (k=0.341), fatigue (k=0.294), anxiety (k=0.289) and breathlessness (k=0.210). Estimation of greater patient symptom burden by carers relative to patients themselves was associated with non-spousal patient–carer relationship, non-cohabitating patients and carers, carer symptoms of anxiety and depression and more carer unmet support needs. Greater symptom burden estimation by the patient relative to the carer was associated with younger patients and longer duration of COPD. Conclusion: Overall, agreement between patients and carers was fair to moderate and was poorer for more subjective symptoms. There is a need to encourage open dialogue between patients and carers to promote shared understanding, help patients express themselves and encourage carers to draw attention to symptoms that patients do not report. The findings suggest a need to screen for and address both the psychological morbidities in patients with advanced COPD and their carers and unmet support needs in carers. Keywords: COPD, informal carers, symptom, agreement

Chronic obstructive pulmonary disease (COPD) is an incurable disease of high prevalence and is the third leading cause of death worldwide [1]. The disease is characterised by progressive breathlessness that in advanced cases, causes intractable breathlessness, a significantly impaired quality of life, progressive disability, and increased and premature mortality., Access to lung volume reduction for advanced emphysema http://ow.ly/Iqru30jbvbE

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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.

Background: Ambulatory capnometers can be relatively unreliable due to condensation from breath. The development of a new ambulatory capnometer (N-Tidal) brings advantages through a novel optical system that also increases accuracy over the range of concentration of carbon dioxide (CO2) in tidal breathing. Aim: Demonstrate the reproducibility of common parameters used in capnography via a novel capnometer. Introduce the measurement of lowest CO2 from an exhaled breath (exBL) Methods: 30 COPD patients were recruited to the pilot trial. Tidal exhaled CO2 was performed daily for 6 weeks. There was 84% device compliance. 7 COPD patients were excluded (6 exacerbation, 1 incorrect use of the device). 6 healthy individuals also recruited. Results:Table 1 provides reproducibility of the parameters measured in COPD patients. exBL is higher in COPD patients (Table 1) than in healthy controls median (CV) 0.20kPa (31%). Conclusions: A novel device for monitoring exhaled CO2 has been demonstrated to be reliable and reproducible for use in patients with COPD. We have demonstrated that COPD patients have a greater low-point of exhaled CO2 than healthy controls which will have an added impact on the sensation of breathlessness in this patient group through CO2 rebreathing.

Heme is a ubiquitous compound of human tissues, and it is involved in cellular physiology and metabolism. Once released from the cell, free heme oxidizes to the ferric state (hemin). High levels of hemin can cause oxidative stress and inflammation if not neutralized immediately by specialized scavenger proteins. Human alpha1-antitrypsin (A1AT), an acute-phase glycoprotein and important inhibitor of neutrophil proteases, is also a hemin-binding protein. A short-term exposure of freshly isolated human blood neutrophils to 4 µM hemin results in cell spreading, surface expression of filament protein, vimentin, free radical production, expression of heme oxygenase-1 (HO-1), release of IL-8, and enhanced neutrophil adhesion to human endothelial cells. Consequently, the phosphorylation of protein kinase C (PKC) occurs after 25 min. Under the same experimental conditions, addition of 1 mg/ml A1AT markedly reduces or abolishes neutrophil-activating effects of hemin and prevents PKC phosphorylation. In a mouse model of acute kidney injury (AKI) plus injection of hemin, monotherapy with 4 mg/mouse A1AT significantly lowered serum levels of free hemin at 2 h after surgery. Moreover, a tendency toward lower AKI scores, reduced infiltration of neutrophils, and lower levels of serum chemokine [CXCL1/keratinocyte-derived chemokine (KC)] was observed. Our findings highlight A1AT as a potential serum scavenger of hemin and suggest that the commercial preparations of human plasma A1AT might prove to be useful therapeutics in conditions associated with hemolysis.

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Context Carers' needs in advanced disease, and specifically in relation to breathlessness, are well evidenced. Publications on educational interventions for carers of patients with advanced disease that focus on symptoms are scarce and absent for breathlessness. Objectives To establish current education provided by clinicians for carers of patients with breathlessness in advanced disease, views about educating carers about breathlessness, and relevant outcomes for a future randomized controlled trial of an educational intervention for carers. Methods An online survey was completed by 365 clinicians: medical, nursing, and allied health professionals from primary care, hospital, and hospice. Descriptive statistics summarized respondent characteristics and survey responses, and the Chi-squared test was applied. Content analysis of free-text comments was conducted. Results Most clinicians reported educating carers by educating patients at clinical contacts with patients. Carer involvement was largely an ‘add-on'; an active carer education strategy, where all carers were invited to attend, was not currently apparent. Clinicians endorsed the importance of educating carers about breathlessness through increasing carer confidence and/or control, helping patients' better self-manage breathlessness and potentially reducing admissions. Joint education with patients, giving practical advice, and strategies for helping patients were advised. To inform a future trial, clinicians identified improvement in patient outcomes, particularly patient quality of life as very important in enhancing clinician adoption of an educational intervention for carers. Conclusion This survey revealed an appetite among clinicians for an educational intervention for carers of patients with breathlessness in advanced disease and provided important insights to underpin a future Phase II randomized controlled trial.

Animal models have been important in understanding the pathogenesis and treatment of chronic obstructive pulmonary disease (COPD). In the early 1960s, the discovery of severe alpha-1 antitrypsin deficiency (AATD) in individuals with COPD and the development of the first animal model for emphysema underpinned the proteinase–antiproteinase hypothesis of the pathogenesis of emphysema. Early studies in animals have contributed significantly to establishing neutrophil elastase as a key proteolytic enzyme involved in alveolar destruction leading to emphysema. The lack of a gene deleted mouse for antitrypsin (AT) would seem to limit the utilization of animal models for studying severe antitrypsin deficiency. However, the use of animal models in combination with other established tools, such as cell biology, epidemiology, and biochemistry can greatly aid an understanding of the pulmonary pathobiology in Z-AT homozygotes. More recently, potential gene-environmental interactions have been assessed with genetically modified animal models to aid understanding of the variability in clinical phenotype and identify potential novel pathways of lung disease in association with the Z antitrypsin protein. Furthermore, research utilizing animals has also contributed to a better knowledge of functions of antitrypsin in health and disease.

$\textbf{Introduction:}$ Breathlessness is a common symptom of advanced disease placing a huge burden on patients, health systems and informal carers (families and friends providing daily help and support). It causes distress and isolation. Carers provide complex personal, practical and emotional support yet often feel ill-prepared to care. They lack knowledge and confidence in their caring role. The need to educate carers and families about breathlessness is established, yet we lack robustly developed carer-targeted educational interventions to meet their needs. $\textbf{Methods:}$ We conducted a qualitative interview study with twenty five purposively-sampled patient-carer dyads living with breathlessness in advanced disease (half living with advanced cancer and half with advanced chronic obstructive pulmonary disease (COPD). We sought to identify carers' educational needs (including what they wanted to learn about) and explore differences by diagnostic group in order to inform an educational intervention for carers of patients with breathlessness in advanced disease. $\textbf{Results:}$ There was a strong desire among carers for an educational intervention on breathlessness. Six key topics emerged as salient for them: 1) understanding breathlessness, 2) managing anxiety, panic and breathlessness, 3) managing infections, 4) keeping active, 5) living positively and 6) knowing what to expect in the future. A cross-cutting theme was relationship management: there were tensions within dyads resulting from mismatched expectations related to most topics. Carers felt that knowledge-gains would not only help them to support the patient better, but also help them to manage their own frustrations, anxieties, and quality of life. Different drivers for education need were identified by diagnostic group, possibly related to differences in caring role duration and resulting impacts. $\textbf{Conclusion:}$ Meeting the educational needs of carers requires robustly developed and evaluated interventions. This study provides the evidence-base for the content of an educational intervention for carers of patients with breathlessness in advanced disease.

Background & Aims Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation-associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD. Methods We collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung- and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant. Results Serum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%–36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or γ-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter ≥280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very-low-density lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Z-overexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. Conclusions In studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosis and impaired lipid secretion. We identified factors associated with significant liver fibrosis in patients, which could facilitate hepatologic assessment and counseling of individuals who carry the Pi*ZZ mutation. ClinicalTrials.gov Number NCT02929940 .

Introduction Lung volume reduction surgery (LVRS) and endobronchial valves (EBV) are NICE approved therapies for advanced COPD. Patient selection is complex but essential for good outcomes. A multidisciplinary team (MDT) comprising a thoracic surgeon, COPD physician, interventionalist, transplant physician and radiologist all contribute to effective patient selection. Our approach involves initial review of CT and lung function to decide on specialist clinic review (SCR) and if potentially suitable for LVR, progressing to MDT discussion. Aim We report on our experiences of a regional COPD Hyperinflation service. Methods Retrospective review of all referrals for LVR received in 2015. Results Out of 123 referrals received, 26 patients are awaiting their review. Five patients did not attend. 92 patients had SCR. 18 of these are undergoing investigations. 20 of the 74 who completed SCR did not fulfil NICE criteria, 54 (73%) were discussed at MDT. Thirty-eight patients out of those having SCR were deemed suitable for LVR or transplantation; (EBV 11%; EBV or LVRS 19%; LVRS 16%; EBV bridge to lung transplantation 3%; endobronchial coil 1%; lung transplant 1%). Fourteen patients were not offered treatments (18.9%). Two patients required further tests and MDT re-discussion. In total, the MDT reviewed 59% of referred patients and offered treatment to 73%. Conclusion Our model of care successfully demonstrates that LVR can be embedded into existing pathways for COPD, improving access to potential therapy that could improve quality of life. Triaging patients at various points and specialist interdisciplinary team input ensures efficient and high quality discussion at a specialist Hyperinflation MDT.

Severe deficiency of the major anti-elastase α 1 -antitrypsin (AT) due to the Z(E342K) variant (Z-AT) is the commonest genetic reason for COPD development. Oxidative stress is associated with Z-AT phenotype. We studied the relationship between oxidative stress and TGF-β1-mediated fibrosis in Z-AT cells. Normal human bronchial epithelial (NHBE) cells transfected with the human Z-AT gene (Z-AT cells) or M-AT gene (M-AT cells) were challenged with LPS (20 ng) to generate oxidative stress and assessed at 24h using ELISA, immunoblot, RT-PCR for oxidant burden (F 2 -Isoprostane), total glutathione (GSH) and oxidised GSH (GSSG), TGF-β1, Smad 2 andα1(I) collagen. TGF-β1 inhibitor (tetramethylthiourea, TMTU)was used to probe the effect of oxidative stress on TGF-β1 pathway. Oxidant stressed Z-AT when compared to oxidant stressed M-AT cells had increased F 2 -Isoprostane (mean±SEM, 187±19 pg/ml vs. 86±18, P=0.003), reduced GSH (0.057±0.01 μM/ml vs. 0.15±0.01, P=0.002), increased GSSG (0.08±0.002 μM/ml vs. 0.05±0.002, P=0.037), Z-AT was associated with upregulated mRNA for; TGF-β1 (band density, mean±SEM, 1.1±0.1 vs. 0.6±0.03, P=0.006), Smad 2 (0.9±0.1 vs. 0.7±0.03, P=0.004) andα1(I) collagen (0.9±0.1 vs. 0.5±0.1, P 2 -Isoprostane (P=0.001), increased GSH (P=0.001), decreased GSSG (P

Background & Aims The Z variant (Glu342Lys) of α 1 -antitrypsin (AT) polymerizes and accumulates in the hepatocyte endoplasmic reticulum (ER) predisposing to neonatal hepatitis and liver cirrhosis. The resultant secretory defect leaves the lungs vulnerable to elastolysis and early-onset emphysema. Our aim in this study was to evaluate the effect of targeting strand 4a (s4A) as a strategy to inhibit polymerization and restore plasma secretion. Methods HEK293 cells and HepG2 cells were transfected with Z-AT (Z-AT cells) or control M-AT (M-AT cells). The effect of Ac-TTAI-NH 2 (4M), Ac-FLEAIG-NH 2 (6M), and Ac-SEAAASTAVVIA-NH 2 (12M) on preventing and reversing intracellular Z-AT polymers and secretion of AT was evaluated by pulse-chase/immunoprecipitation, ELISA, and immunoblot with a polymer-specific antibody (ATZII). The ER overload response was assessed by RT-PCR for PERK, calnexin, and RGS16, and ELISA for NF-κB, IL-6, and IL-8. Results All peptides prevented the intracellular accumulation of Z-AT (4M>6M>12M) in comparison with control peptides, with detection of the AT–Inhibitor complex in inclusion bodies. In so doing, 4M also significantly increased the concentration of secreted Z-AT and the elastase inhibitory activity. Furthermore, the 4M peptide was able to reverse the intracellular aggregation of Z-AT. The ER accumulation of Z-AT was shown to induce PERK-dependent NF-κB, IL-6, IL-8, and RGS16 and calnexin; all of which could be abrogated effectively by 4M. 4M had no effect on apoptosis or cell viability. Conclusions These findings are the first evidence that targeting s4A can prevent the cellular accumulation and deleterious effects of Z-AT and restore its plasma concentrations. As such, this is a major step towards treatment of patients with Z-AT-related disease.

A rapid recruitment of neutrophils to sites of injury or infection is a hallmark of the inflammatory response and is required for effective host defense against pathogenic stimuli. However, neutrophil-mediated inflammation can also lead to chronic tissue destruction; therefore, a better understanding of the mechanisms underlying neutrophil influx and activation is of critical importance. We have previously shown that the acute phase protein α1-antitrypsin (AAT) inhibits neutrophil chemotaxis. In this study, we examine mechanisms related to the effect of AAT on neutrophil responses. We report a previously unknown function of AAT to inactivate calpain I (μ-calpain) and to induce a rapid cell polarization and random migration. These effects of AAT coincided with a transient rise in intracellular calcium, increase in intracellular lipids, activation of the Rho GTPases, Rac1 and Cdc42, and extra-cellular signal-regulated kinase (ERK1/2). Furthermore, AAT caused a significant inhibition of nonstimulated as well as formyl-met-leu-phe (fMLP)-stimulated neutrophil adhesion to fibronectin, strongly inhibited lipopolysaccharide-induced IL-8 release and slightly delayed neutrophil apoptosis. The results presented here broaden our understanding of the regulation of calpain-related neutrophil functional activities, and provide the impetus for new studies to define the role of AAT and other acute phase proteins in health and disease.

Cholesterol is the most abundant lipid component of the plasma membrane, and thus the equilibrium between free cholesterol and raft cholesterol act as a determinant of raft function and cell signalling. The mechanisms that regulate the lipid raft cholesterol levels are largely unknown. Here we demonstrate that SERPINA1 (alpha1-antitrypsin), an acute phase protein and the classical neutrophil elastase inhibitor, is localized within lipid rafts in primary human monocytes in vitro. SERPINA1 association with monocytes is inhibited by cholesterol depleting/efflux-stimulating agents (nystatin, filipin, MbetaCD (methyl-beta-cyclodextrin) and oxidized low-density lipoprotein (oxLDL) and conversely, enhanced by free cholesterol. Furthermore, SERPINA1/monocyte association per se depletes lipid raft cholesterol as characterized by the activation of extracellular signal-regulated kinase 2, formation of cytosolic lipid droplets, and a complete inhibition of oxLDL uptake by monocytes. Our findings for the first time highlight that the entry and cell association of SERPINA1 is dependent on lipid raft cholesterol and that SERPINA1 depletes lipid raft cholesterol.

α1-antitrypsin deficiency (AATD) significantly increases the risk of developing chronic obstructive pulmonary disease (COPD), and testing of all COPD patients for AATD is recommended by the World Health Organization, European Respiratory Society and Global Initiative for Chronic Obstructive Lung Disease (GOLD). We aimed to determine trends for testing and diagnosing AATD from 1990 to 2014.This study analysed all patients diagnosed with COPD from about 550 UK Optimum Patient Care Research Database general practices, including a subgroup of those diagnosed before the age of 60 years.We identified 107 024 COPD individuals, of whom 29 596 (27.6%) were diagnosed before 60 years of age. Of them, only 2.2% (95% CI 2.09–2.43%) had any record of being tested for AATD. Of those tested, 23.7% (95% CI 20.5–27.1%) were diagnosed with AATD. Between 1994 and 2013 the incidence of AATD diagnosis generally increased. A diagnosis of AATD was associated with being male, being an ex-smoker, more severe COPD with a lower forced expiratory volume in 1 s % pred and higher GOLD 2017 stages (all pDespite an increase in the frequency of AATD testing since 1990, only 2.2% of patients diagnosed with COPD before the age of 60 years were tested. AATD prevalence was 23.7% in those tested. Thus, it appears that AATD remains markedly underdiagnosed in COPD patients.

α1-Antitrypsin (AT) is a major elastase inhibitor within the lung. Oxidation of critical methionine residues in AT generates oxidized AT (Ox-AT), which has a greatly diminished ability to inhibit neutrophil elastase. This process may contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD) by creating a functional deficiency of AT permitting lung destruction. We show here that Ox-AT promotes release of human monocyte chemoattractant protein-1 (MCP-1) and IL-8 from human lung type epithelial cells (A549) and normal human bronchial epithelial (NHBE) cells. Native, cleaved, polymeric AT and secretory leukoproteinase inhibitor (SLPI) and oxidized conformations of cleaved, polymeric AT and SLPI did not have any significant effect on MCP-1 and IL-8 secretion. These findings were supported by the fact that instillation of Ox-AT into murine lungs resulted in an increase in JE (mouse MCP-1) and increased macrophage numbers in the bronchoalveolar lavage fluid. The effect of Ox-AT was dependent on NF-κB and activator protein-1 (AP-1)/JNK. These findings have important implications. They demonstrate that the oxidation of methionines in AT by oxidants released by cigarette smoke or inflammatory cells not only reduces the antielastase lung protection, but also converts AT into a proinflammatory stimulus. Ox-AT generated in the airway interacts directly with epithelial cells to release chemokines IL-8 and MCP-1, which in turn attracts macrophages and neutrophils into the airways. The release of oxidants by these inflammatory cells could oxidize AT, perpetuating the cycle and potentially contributing to the pathogenesis of COPD. Furthermore, these data demonstrate that molecules such as oxidants, antiproteinases, and chemokines, rather than act independently, are likely to interact to cause emphysema.

α1-Antitrypsin (A1AT) purified from human plasma upregulates expression and release of angiopoietin-like protein 4 (Angptl4) in adherent human blood monocytes and in human lung microvascular endothelial cells, providing a mechanism for the broad immune-regulatory properties of A1AT independent of its antiprotease activity. In this study, we demonstrate that A1AT (Prolastin), a potent inducer of Angptl4, contains significant quantities of the fatty acids (FA) linoleic acid (C18:2) and oleic acid (C18:1). However, only trace amounts of FAs were present in preparations that failed to increase Angplt4 expression, for example, A1AT (Zemaira) or M-type A1AT purified by affinity chromatography. FA pull-down assays with Western blot analysis revealed a FA-binding ability of A1AT. In human blood-adherent monocytes, A1AT-FA conjugates upregulated expression of Angptl4 (54.9-fold, p < 0.001), FA-binding protein 4 (FABP4) (11.4-fold, p < 0.001), and, to a lesser degree, FA translocase (CD36) (3.1-fold, p < 0.001) relative to A1AT devoid of FA (A1AT-0). These latter effects of A1AT-FA were blocked by inhibitors of peroxisome proliferator-activated receptor (PPAR) β/δ (ST247) and PPARγ (GW9662). When compared with controls, cell pretreatment with ST247 diminished the effect of A1AT-LA on Angptl4 mRNA (11.6- versus 4.1-fold, p < 0.001) and FABP4 mRNA (5.4- versus 2.8-fold, p < 0.001). Similarly, preincubation of cells with GW9662 inhibited inducing effect of A1AT-LA on Angptl4 mRNA (by 2-fold, p < 0.001) and FABP4 mRNA (by 3-fold, p < 0.001). Thus, A1AT binds to FA, and it is this form of A1AT that induces Angptl4 and FABP4 expression via a PPAR-dependent pathway. These findings provide a mechanism for the unexplored area of A1AT biology independent of its antiprotease properties.

COPD is projected to be the third most common cause of mortality world-wide by 2020((1)). Animal models of COPD are used to identify molecules that contribute to the disease process and to test the efficacy of novel therapies for COPD. Researchers use a number of models of COPD employing different species including rodents, guinea-pigs, rabbits, and dogs((2)). However, the most widely-used model is that in which mice are exposed to cigarette smoke. Mice are an especially useful species in which to model COPD because their genome can readily be manipulated to generate animals that are either deficient in, or over-express individual proteins. Studies of gene-targeted mice that have been exposed to cigarette smoke have provided valuable information about the contributions of individual molecules to different lung pathologies in COPD((3-5)). Most studies have focused on pathways involved in emphysema development which contributes to the airflow obstruction that is characteristic of COPD. However, small airway fibrosis also contributes significantly to airflow obstruction in human COPD patients((6)), but much less is known about the pathogenesis of this lesion in smoke-exposed animals. To address this knowledge gap, this protocol quantifies both emphysema development and small airway fibrosis in smoke-exposed mice. This protocol exposes mice to CS using a whole-body exposure technique, then measures respiratory mechanics in the mice, inflates the lungs of mice to a standard pressure, and fixes the lungs in formalin. The researcher then stains the lung sections with either Gill's stain to measure the mean alveolar chord length (as a readout of emphysema severity) or Masson's trichrome stain to measure deposition of extracellular matrix (ECM) proteins around small airways (as a readout of small airway fibrosis). Studies of the effects of molecular pathways on both of these lung pathologies will lead to a better understanding of the pathogenesis of COPD.

alpha(1)-Antitrypsin (AT) is a major proteinase inhibitor within the lung. The Z variant of AT (E342K) polymerizes within the liver and lung, resulting in hepatic aggregation of AT and tissue deficiency, predisposing to early onset of cirrhosis and emphysema, respectively. Polymerization of the aberrant protein can be prevented in vitro by specific peptides such as FLEAIG. This peptide serves as a lead molecule to design a shorter peptide that may be effective as a therapeutic agent. In this study we employed a systematic chemical approach using alanine scanning of Ac-FLEAIG-OH and subsequent peptide shortening to study the binding of shorter peptides to Z-AT. While two additional 6-mer peptides Ac-FLAAIG-OH and Ac-FLEAAG-OH were found to bind to Z-AT, their daughter peptides Ac-FLEAA-NH(2) and Ac-FLAA-NH(2) also bound avidly to Z-AT and prevented polymerization of the protein. Further comparative studies revealed that the binding of Ac-FLAA-NH(2) was more specific for Z-AT. The peptide-AT complex formation was enhanced by the presence of C-terminal amide group on the peptide, and circular dichroism analysis demonstrated that a random coil rather than a beta-helical conformation favored binding of the peptide to AT. In summary, this study has identified novel small peptides that inhibit Z-AT polymerization, and are a significant advance towards the treatment of Z-AT-related cirrhosis and emphysema.

Chronic obstructive pulmonary disease is a major cause of morbidity and mortality worldwide. The mechanisms by which cigarette smoke leads to the irreversible dilatation and destruction of terminal airspaces of the lung are being unravelled largely as a result of the explosion of studies in animals. At the forefront of this has been the use of genetically manipulated mice, and the evolution and understanding of different models of emphysema. This review will summarise the current models of emphysema.

Summary Recent reports have described the successful use of recombinant factor VIIa in severe diffuse alveolar haemorrhage (DAH). We describe the clinical course of a young man with catastrophic recurrent idiopathic alveolar haemorrhage that was resistant to immunosuppression and recombinant factor VIIa. The bleeding only ceased following administration of high-dose intravenous immunoglobulins (IVIg). The case was subsequently complicated by bilateral pulmonary thromboemboli (PTE) requiring anticoagulation. This case is the first to clearly associate a benefit from IVIg therapy with an improvement in DAH. Furthermore it illustrates the difficulties in managing a patient with life-threatening alveolar haemorrhage and the subsequent thrombotic complications that may have been related to the therapy.