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Objective: Alpha-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., Design: Baseline 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., Results: Among 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., Conclusion: Our 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Augmentation therapy (AT) is the only specific treatment licensed for patients with alpha-1 antitrypsin deficiency (AATD) associated lung disease. Since patients with severe AATD may have a very different prognosis and AT requires intravenous infusions for life, the decision to initiate AT may be challenging., Methods: This survey was conducted on 63 experts in AATD from 13 European countries about their opinions and attitudes regarding AT. Participants were asked to rank the importance of 11 identified factors related with the prescription of AT. In addition, each participant was asked to respond to the indication of AT for 30 out of 500 hypothetical cases developed with the combinations of the 11 factors. Each case was evaluated by 3 experts to check the concordance., Results: The variables that scored higher on preferences for initiating AT were AAT genotype (score 8.6 from a Likert scale 0-10 (SD: 1.7)), AATD serum level (8.2 (SD:2.4)) and FEV1 (%) decline (7.9 (SD:2.4)). Among the 500 different cases, there was an agreement in indication of AT among the 3 experts in 291 (58.2%). Regarding the variables associated with AT, it was indicated to 81.9% of Pi*ZZ, 52.4% of Pi*SZ and 9.8% of Pi*MZ (p < 0.0001). For Pi*ZZ patients, multivariate analysis identified younger age, reduced FEV1 (%), higher FEV1 decline and worse emphysema as significantly associated with prescription (AUC = 0.8114); for Pi*SZ variables were younger age, worse FEV1 (%) and worse emphysema (AUC = 0.7414); and for Pi*MZ younger age, worse DLCO (%), higher DLCO decline and dyspnea (AUC = 0.8387)., Conclusion: There is a high variability in the criteria for prescription of AT among European experts. Most cases were recommended AT according to guidelines, but a significant number of patients with genotype Pi*SZ and almost 10% Pi*MZ were recommended to initiate AT despite the lack of evidence of efficacy in these genotypes., Competing Interests: Timm Greulich reports grants from CSL-Behring, grants from Grifols, grants from Kamada, during the conduct of the study; personal fees from Astra Zeneca, personal fees from Berlin-Chemie, personal fees from Boehringer-Ingelheim, personal fees from Chiesi, personal fees from CSL-Behring, grants and personal fees from Grifols, personal fees from GSK, personal fees from Novartis, grants from German Centre for Lung Research (DZL), Marburg, Germany (Deutsches Zentrum für Lungenforschung), outside the submitted work. Christian Clarenbach received advisory fees from Roche, Novartis, Boehringer, GSK, Astra Zeneca, Sanofi, Vifor, OM Pharma, Grifols and Mundipharma. María L Torres-Duran has received speaker and consulting fees from CSL Behring and Grifols. Alice M Turner has received either grants or speaker fees from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Chiesi, CSL Behring, Takeda, Vertex and Grifols Biotherapeutics. Marc Miravitlles has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Sandoz, Zambon, CSL Behring, Grifols and Novartis, consulting fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, Spin Therapeutics, ONO Pharma, pH Pharma, Palobiofarma SL, Takeda, Novartis, Sanofi and Grifols and research grants from Grifols. The authors report no other conflicts of interest in this work., (© 2022 Greulich et al.)

Background: Half of acute exacerbations of COPD are due to bacterial infection, and the other half are likely influenced by microbial colonisation. The same organisms commonly cultured during acute exacerbations are often found in the sputum of patients during stability. A robust assessment of the prevalence of potentially pathogenic microorganisms (PPMs) in the sputum of stable COPD patients may help to inform the targeted prevention of exacerbation by these organisms., Methods: A systematic review and meta-analysis was carried out to determine the prevalence of PPMs in patients with COPD in the stable state. Meta-analysis of prevalence was carried out using the Freeman-Tukey double arcsine transformation random effects model, and sub-group analysis was performed for sputum modality. Prevalence of total and individual PPMs was calculated from patient-level data from individual studies., Results: Pooled prevalence of PPMs identified by sputum culture was found to be 41% (95% CI 36-47%). Significant heterogeneity was found across all studies, which can likely be attributed to inconsistent measuring and reporting of PPMs. The most commonly reported organisms were H. influenzae , M catarrhalis , S. pneumoniae , S. aureus , and P. aeruginosa . Declining lung function was weakly correlated with prevalence of PPMs., Conclusion: The airways of patients with COPD are colonised with PPMs during the stable state in almost half of patients. A complex relationship likely exists between the microbiome in the stable state and the phenotype of COPD patients. Targeted microbial therapy for preventing exacerbations of COPD should carefully consider the stable microbiome as well as the exacerbated.

Background: The use of ward-based noninvasive ventilation (NIV) for acute hypercapnic respiratory failure (AHRF) unrelated to chronic obstructive pulmonary disease (COPD) remains controversial. This study evaluated the outcomes and failure rates associated with NIV application in the ward-based setting for patients with AHRF unrelated to COPD., Methods: A multicentre, retrospective cohort study of patients with AHRF unrelated to COPD was conducted. COPD was not the main reason for hospital admission, treated with ward-based NIV between February 2004 and December 2018. All AHRF patients were eligible; exclusion criteria comprised COPD patients, age < 18 years, pre-NIV pH < 7.35, or a lack of pre-NIV blood gas. In-hospital mortality was the primary outcome; univariable and multivariable models were constructed. The obesity-related AHRF group included patients with AHRF due to obesity hypoventilation syndrome (OHS), and the non-obesity-related AHRF group included patients with AHRF due to pneumonia, bronchiectasis, neuromuscular disease, or fluid overload., Results: In total, 479 patients were included in the analysis; 80.2% of patients survived to hospital discharge. Obesity-related AHRF was the indication for NIV in 39.2% of all episodes and was the aetiology with the highest rate of survival to hospital discharge (93.1%). In the multivariable analysis, factors associated with a higher risk of in-hospital mortality were increased age (odds ratio, 95% CI: 1.034, 1.017-1.051, P < 0.001) and pneumonia on admission (5.313, 2.326-12.131, P < 0.001). In the obesity-related AHRF group, pre-NIV pH < 7.15 was associated with significantly increased in-hospital mortality (7.800, 1.843-33.013, P =0.005); however, a pre-NIV pH 7.15-7.25 was not associated with increased in-hospital mortality (2.035, 0.523-7.915, P =0.305)., Conclusion: Pre-NIV pH and age have been identified as important predictors of surviving ward-based NIV treatment. Moreover, these data support the use of NIV in ward-based settings for obesity-related AHRF patients with pre-NIV pH thresholds down to 7.15. However, future controlled trials are required to confirm the effectiveness of NIV use outside critical care settings for obesity-related AHRF., Competing Interests: Prof. Turner reports grants from ResMed and Philips outside the submitted work. Dr. Mukherjee reports personal fees and nonfinancial support from Pfizer, personal fees from Boehringer Ingelheim, and personal fees from ResMed, outside the submitted work. Otherwise, the authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2021 Bandar M. Faqihi et al.)

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 FEV 1 % 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 .

A concern of antibiotic use in chronic obstructive pulmonary disease (COPD) is the emergence and propagation of antimicrobial resistance (AMR). A systematic review was conducted to determine prevalence, pattern, risk factors and consequences of AMR in COPD. Bibliographic databases were searched from inception to November 2020, with no language restrictions, including studies of any design that included patients with COPD and reported prevalence and pattern of AMR. 2748 unique titles and abstracts were identified, of which 63 articles, comprising 26,387 patients, met inclusion criteria. Forty-four (69.8%) studies were performed during acute exacerbation. The median prevalence of AMR ranged from 0-100% for Pseudomonas aeruginosa, Moraxella catarrhalis, Klebsiella pneumoniae and Acinetobacter baumannii . Median resistance rates of H influenzae and S pneumoniae were lower by comparison, with maximum rates ≤40% and ≤46%, respectively, and higher for Staphylococcus aureus . There was a trend towards higher rates of AMR in patients with poorer lung function and greater incidence of previous antibiotic exposure and hospitalisation. The impact of AMR on mortality was unclear. Data regarding antimicrobial susceptibility testing techniques and the impact of other risk factors or consequences of AMR were variable or not reported. This is the first review to systematically unify data regarding AMR in COPD. AMR is relatively common and strategies to optimise antibiotic use could be valuable to prevent the currently under-investigated potential adverse consequences of AMR.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.2000957 .

Alpha 1 Antitrypsin deficiency (AATD) is a hereditary condition characterized by low serum Alpha 1 Antitrypsin (AAT) levels and a predisposition towards early-onset emphysema. Infusion of AAT is the only disease-modifying therapy that can sufficiently raise plasma AAT levels above the putative protective threshold and reduce the decline in lung density loss. Several randomized controlled trials (RCTs) and registry studies support the clinical efficacy of AAT therapy in slowing the progression of AATD-related emphysema and improving survival outcomes. The COVID-19 pandemic has prompted physicians to develop additional strategies for delivering AAT therapy, which are not only more convenient for the patient, but are "COVID-19 friendly", thereby reducing the risk of exposing these vulnerable patients. Intravenous (IV) self-administration of AAT therapy is likely to be beneficial in certain subgroups of patients with AATD and can remove the need for weekly hospital visits, thereby improving independence and well-being. Increasing the awareness of self-administration in AATD through the development of formal guidelines and training programs is required among both physicians and patients and will play an essential role, especially post-COVID-19, in encouraging physicians to consider self-administration for AATD in suitable patients. This review summarizes the benefits of AAT therapy on the clinical endpoints of mortality and quality of life (QoL) and discusses the benefits of self-administration therapy compared with conventional therapy administered by a healthcare professional. In addition, this review highlights the challenges of providing AAT therapy during the COVID-19 pandemic and the potential considerations for its implementation thereafter., Competing Interests: RA Sandhaus has received honoraria, research funding, and/or travel reimbursement from CSL Behring, Grifols, Vertex, AstraZeneca, Takeda, Dicerna, Arrowhead, Inhibrx and the US National Institutes of Health. AM Turner has received grant funding and/or honoraria from CSL Behring, Grifols and Vertex within the last 5 years. M Sucena has received consulting fees for lectures and participation in advisory boards from Bial, Boehringer Ingelheim, CSL Behring, Grifols and Novartis. FJF Herth reports personal fees from CSL, during the conduct of the study. T Greulich reports personal fees from CSL-Behring, grants from Grifols, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2021 Herth et al.)

The effectiveness of bi-level positive airway pressure (BiPAP) in patients with acute hypercapnic respiratory failure (AHRF) due to etiologies other than chronic obstructive pulmonary disease (COPD) is unclear. To systematically review the evidence regarding the effectiveness of BiPAP in non-COPD patients with AHRF. The Cochrane Library, MEDLINE, EMBASE, and CINAHL Plus were searched according to prespecified criteria (PROSPERO-CRD42018089875). Randomized controlled trials (RCTs) assessing the effectiveness of BiPAP versus continuous positive airway pressure (CPAP), invasive mechanical ventilation, or O 2 therapy in adults with non-COPD AHRF were included. The primary outcomes of interest were the rate of endotracheal intubation (ETI) and mortality. Risk-of-bias assessment was performed, and data were synthesized and meta-analyzed where appropriate. Two thousand four hundred and eighty-five records were identified after removing duplicates. Eighty-eight articles were identified for full-text assessment, of which 82 articles were excluded. Six studies, of generally low or uncertain risk-of-bias, were included involving 320 participants with acute cardiogenic pulmonary edema (ACPO) and solid tumors. No significant differences were seen between BiPAP ventilation and CPAP with regard to the rate of progression to ETI (risk ratio [RR] = 1.49, 95% confidence interval [CI], 0.63-3.62, P = 0.37) and in-hospital mortality rate (RR = 0.71, 95% CI, 0.25-1.99, P = 0.51) in patients with AHRF due to ACPO. The efficacy of BiPAP appears similar to CPAP in reducing the rates of ETI and mortality in patients with AHRF due to ACPO. Further research on other non-COPD conditions which commonly cause AHRF such as obesity hypoventilation syndrome is needed., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Annals of Thoracic Medicine.)

Objectives: To examine the accuracy and cost-effectiveness of various chronic obstructive pulmonary disease (COPD) screening tests and combinations within a Chinese primary care population., Design: Screening test accuracy study., Setting: Urban and rural community health centres in four municipalities of China: Beijing (north), Chengdu (southwest), Guangzhou (south) and Shenyang (northeast)., Participants: Community residents aged 40 years and above who attended community health centres for any reason were invited to participate. 2445 participants (mean age 59.8 (SD 9.6) years, 39.1% (n=956) male) completed the study (February-December 2019), 68.9% (n=1684) were never-smokers and 3.6% (n=88) had an existing COPD diagnosis. 13.7% (n=333) of participants had spirometry-confirmed airflow obstruction., Interventions: Participants completed six index tests (screening questionnaires (COPD Diagnostic Questionnaire, COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk (CAPTURE), Chinese Symptom-Based Questionnaire (C-SBQ), COPD-SQ), microspirometry (COPD-6), peak flow (model of peak flow meters used in the study (USPE)) and the reference test (ndd Easy On-PC)., Primary and Secondary Outcomes: Cases were defined as those with forced expiratory volume in one second (FEV 1 )/forced vital capacity (FVC) below the lower limit of normal (LLN-GLI) on the reference test. Performance of individual screening tests and their combinations was evaluated, with cost-effectiveness analyses providing cost per additional true case detected., Results: Airflow measurement devices (sensitivities 64.9% (95% CI 59.5% to 70.0%) and 67.3% (95% CI 61.9% to 72.3%), specificities 89.7% (95% CI 88.4% to 91.0%) and 82.6% (95% CI 80.9% to 84.2%) for microspirometry and peak flow, respectively) generally performed better than questionnaires, the most accurate of which was C-SBQ (sensitivity 63.1% (95% CI 57.6% to 68.3%) specificity 74.2% (95% CI 72.3% to 76.1%)). The combination of C-SBQ and microspirometry used in parallel maximised sensitivity (81.4%) (95% CI 76.8% to 85.4%) and had specificity of 68.0% (95% CI 66.0% to 70.0%), with an incremental cost-effectiveness ratio of £64.20 (CNY385) per additional case detected compared with peak flow., Conclusions: Simple screening tests to identify undiagnosed COPD within the primary care setting in China is possible, and a combination of C-SBQ and microspirometry is the most sensitive and cost-effective. Further work is required to explore optimal cut-points and effectiveness of programme implementation., Trial Registration Number: ISRCTN13357135., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The pulmonary endothelium is dysfunctional in chronic obstructive pulmonary disease (COPD), a known risk factor for lung cancer. The pulmonary endothelium is altered in emphysema, which is disproportionately affected by cancers. Gene and microRNA expression differs between COPD and non-COPD lung. We hypothesised that the alteration in microRNA expression in the pulmonary endothelium contributes to its dysfunction. A total of 28 patients undergoing pulmonary resection were recruited and endothelial cells were isolated from healthy lung and tumour. MicroRNA expression was compared between COPD and non-COPD patients. Positive findings were confirmed by quantitative polymerase chain reaction (qPCR). Assays assessing angiogenesis and cellular migration were conducted in Human Umbilical Vein Endothelial Cells ( n = 3-4) transfected with microRNA mimics and compared to cells transfected with negative control RNA. Expression of miR-181b-3p, miR-429 and miR-23c (all p < 0.05) was increased in COPD. Over-expression of miR-181b-3p was associated with reduced endothelial sprouting ( p < 0.05). miR-429 was overexpressed in lung cancer as well and exhibited a reduction in tubular formation. MicroRNA-driven changes in the pulmonary endothelium thus represent a novel mechanism driving emphysema. These processes warrant further study to determine if they may be therapeutic targets in COPD and lung cancer.

Sputum colour may mark bacterial involvement in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, whether colour vision deficiency (CVD) in COPD patients could impact the use of sputum colour charts as part of a guide to antibiotic use in exacerbations is unknown. This study used an exploratory mixed-method approach to establish the likelihood that COPD patients will be colour blind and whether this would result in the sputum colour chart being unusable in the context of the patients' self-management of their condition. CVD is under-reported in primary care and comorbidities in COPD patients increase the risk of acquiring CVD. Participants diagnosed with CVD and risk of acquiring CVD were able to use the sputum colour charts. Colour charts are likely to be usable even in the context of undiagnosed CVD in COPD patients.

Background: There is partial evidence that COPD is expressed differently in women than in men, namely on symptoms, pulmonary function, exacerbations, comorbidities or prognosis. There is a need to improve the characterization of COPD in females., Methods: We obtained and pooled data of 17 139 patients from 22 COPD cohorts and analysed the clinical differences by sex, establishing the relationship between these characteristics in women and the prognosis and severity of the disease. Comparisons were established with standard statistics and survival analysis, including crude and multivariate Cox-regression analysis., Results: Overall, 5355 (31.2%) women were compared with men with COPD. Women were younger, had lower pack-years, greater FEV 1 %, lower BMI and a greater number of exacerbations (all p < 0.05). On symptoms, women reported more dyspnea, equal cough but less expectoration (p < 0.001). There were no differences in the BODE index score in women (2.4) versus men (2.4) (p = 0.5), but the distribution of all BODE components was highly variable by sex within different thresholds of BODE. On prognosis, 5-year survival was higher in COPD females (86.9%) than in males (76.3%), p < 0.001, in all patients and within each of the specific comorbidities that we assessed. The crude and adjusted RR and 95% C.I. for death in males was 1.82 (1.69-1.96) and 1.73 (1.50-2.00), respectively., Conclusions: COPD in women has some characteristic traits expressed differently than compared to men, mainly with more dyspnea and COPD exacerbations and less phlegm, among others, although long-term survival appears better in female COPD patients., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Lung resection remains the gold standard treatment for early stage lung cancer; prediction of postoperative lung function is a key selection criterion for surgery with the aim of determining risk of postoperative dyspnoea. We aimed to identify the different prediction techniques used, and compare their accuracy., Methods: A systematic review and meta-analysis sought to synthesise studies conducted that assess prediction of postoperative lung function up to 18/02/2018 (n = 135). PROBAST was used to assess risk of bias in studies, 17 studies were judged to be at low risk of bias., Findings: Meta-analysis revealed CT volume and density measurement to be the most accurate (mean difference 71 ml) and precise (standard deviation 207 ml) of the reported techniques used for predicting FEV1; evidence for predicting gas transfer was lacking., Interpretation: The evidence suggests using CT volume and density is the preferred technique in the prediction of postoperative FEV1. Further studies are required to ensure that the methods and thresholds we propose are linked to patient reported outcomes., Funding: Salary support for NKO, RM, PN, BN, and AMT was provided by University Hospitals Birmingham NHS Foundation Trust., Competing Interests: AMT reports grants from Grifols Biotherapeutics, grants from Alpha-1 Foundation, personal fees from CSL Behring, grants and non-financial support from Arrowhead Inc, outside the submitted work. NKO, JH-S, RM, PN, and BN have no conflict of interest to declare., (© 2019 Published by Elsevier Ltd.)

Purpose: The purpose of this paper is to investigate patient perspectives on attending pulmonary rehabilitation (PR). This qualitative case study identifies the benefits and challenges to attending PR and presents areas of improvements as recommended by patients., Design/methodology/approach: A qualitative case study of a UK case study based on a PR programme based on undertaking focus groups ( n =3) and interviews ( n =15) with current and former patients., Findings: The findings report patient perspectives of the challenges and benefits of attending a PR programme along with recommendations on how the service could be improved., Research Limitations/implications: The authors focussed solely on a UK PR programme, so the findings might not be applicable to other countries if PR is organised and provided in a unique way or setting., Practical Implications: This paper provides valuable insights to patient perspectives offrom patients attending PR programmes, which are useful to those running and designing these services., Originality/value: The findings identify the benefits and challenges for patients attending PR programmes and suggest areas where improvements can be made.

Introduction: Non-invasive ventilation (NIV) is recommended for treatment of acute hypercapnic respiratory failure (AHRF) refractory to medical management in patients with COPD. This study investigated the relationship between time from hospital presentation to diagnosis of AHRF and in-hospital mortality., Methods: Retrospective analysis of hospitalised COPD patients treated with a first episode of ward-based NIV for AHRF at a large UK teaching hospital between 2004 and 2017. Data collected prospectively as part of NIV service evaluation. Multivariable logistic regression performed to identify predictors of in-hospital mortality., Results: In total, 547 unique patients were studied comprising 245 males (44.8%), median age 70.6 years, median FEV1% predicted 34%. Overall in-hospital mortality was 19% (n = 104); median survival was 1.7 years. In univariate analysis, a longer time between hospital presentation to diagnosis of AHRF was associated with in-hospital mortality (median [IQR]: 8.7 [0.7-75.8] hours vs. 1.9 [0.3-13.6] hours, p < 0.0001). In multivariable logistic regression, significant predictors of in-hospital mortality were AHRF >24 h after hospital presentation (odds ratio [95% CI]: 2.29 [1.33-3.95], p = 0.003), pneumonia on admission (1.81 [1.07-3.08], p = 0.027), increased age (1.10 [1.07-1.14], p < 0.001) and NIV as ceiling of treatment (5.86 [2.87-11.94], p < 0.001)., Conclusions: Hospitalised COPD patients with late presentation of AHRF, requiring acute ward-based NIV, may have increased in-hospital mortality. These patients may benefit from closer monitoring and earlier specialist respiratory review., (Copyright © 2019. Published by Elsevier Ltd.)

Purpose: In the critically ill, sarcopenia is associated with a variety of adverse outcomes however there is no consensus regarding its management. This study aimed to systematically review the evidence for interventions for the management and prevention of sarcopenia in critically ill patients., Materials and Methods: Bibliographic databases were searched according to pre-specified criteria (PROSPERO-CRD42018086271). Randomised controlled trials (RCTs) investigating interventions to preserve muscle mass and/or function in critically ill patients were included. Two independent authors selected the articles and assessed bias using the Cochrane Risk of Bias Tool., Results: Twenty-two eligible RCTs were identified comprising 2792 patients. Three main groups of interventions were implemented in these trials: neuromuscular electrical stimulation (NMES), exercise-based and nutritional. Both the interventions and outcomes measured varied significantly between studies. NMES was most frequently studied as an intervention to preserve muscle mass whilst exercise-based treatments were evaluated as interventions to preserve muscle function. There was significant variation in the efficacy of the interventions on sarcopenia markers and secondary outcomes., Conclusions: NMES and exercise-based interventions may preserve muscle mass and function in patients with critical illness. There is a lack of consistency seen in the effects of these interventions. Further, large, high quality RCTs are required., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Despite recent improvements, α 1 -antitrypsin deficiency (AATD) remains a rarely diagnosed and treated condition. To assess the variability of AATD diagnosis/treatment in Europe, and to evaluate clinicians' views on methods to optimise management, specialist AATD clinicians were invited to complete a web-based survey. Surveys were completed by 15 physicians from 14 centres in 13 European countries. All respondents perceived the AATD diagnosis rate to be low in their country; 77% of physicians believed that ∼15% of cases were diagnosed. Low awareness was perceived as the greatest barrier to diagnosis. Spirometry was considered more practical than quantitative computed tomography (QCT) for monitoring AATD patients in clinical practice; QCT was considered more useful in trials. AAT therapy provision was reported to be highly variable: France and Germany were reported to treat the highest proportion (∼60%) of diagnosed patients, in contrast to the UK and Hungary, where virtually no patients receive AAT therapy. Most clinicians supported self-administration and extended dosing intervals to improve convenience of AAT therapy. This survey indicates that AATD diagnosis and management are highly heterogeneous in Europe; European cooperation is essential to generate data to support access to AAT therapy. Improving convenience of AAT therapy is an ongoing objective., Competing Interests: Conflict of interest: I. Horváth reports personal fees from AstraZeneca, GSK, Sandoz, Sager Pharma, Orion and Affidea, personal fees and non-financial support from Boehringer-Ingelheim, Berlin-Chemie, Novartis, CSL Behring, Roche and Teva, and non-financial support from MSD, outside the submitted work. Conflict of interest: J. Chlumský reports fees for lectures and consultancy from CSL Behring. Conflict of interest: J. Chorostowska-Wynimko reports grants, personal fees, nonfinancial support and other support from Grifols and CSL Behring, personal fees from Kamada, and other support from Shire, outside the submitted work. Conflict of interest: L. Corda reports personal fees from Grifols and CSL Behring for lectures, speakers’ bureaus and expert testimony. Conflict of interest: J.H. Ficker reports grants from CSL Behring during the conduct of the study; and personal fees from Grifols, and personal fees and non-financial support from CSL Behring, outside the submitted work. Conflict of interest: M. Kneussl has nothing to disclose. Conflict of interest: M. Miravitlles reports speaker's fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Zambon, CSL Behring, Grifols and Novartis, consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, Mereo Biopharma, Verona Pharma, TEVA, pH Pharma, Novartis and Grifols, and grants from GlaxoSmithKline and Grifols, outside the submitted work. Conflict of interest: G. Thabut reports personal fees and non-financial support from CSL Behring, and grants, personal fees and non-financial support from LFB, outside the submitted work. Conflict of interest: A.M. Turner reports consultancy fees from CSL Behring, grants from Grifols Biotherapeutics, the Alpha 1 Foundation, the ATS Foundation and the Chest Foundation, grants, conference attendance and fees for clinical trial work as investigator paid to her institution from Arrowhead Inc., and fees for work as study investigator paid to her institution from Boehringer, outside the submitted work. Conflict of interest: N.G. McElvaney reports grants and personal fees from CSL Behring, grants, and personal fees and non-financial support from Grifols, outside the submitted work. Conflict of interest: E. Derom has nothing to disclose. Conflict of interest: E. van 't Wout has nothing to disclose. Conflict of interest: M. Canotilho has nothing to disclose. Conflict of interest: M. Sucena has nothing to disclose.

The CODEX index was developed and validated in patients hospitalized for COPD exacerbation to predict the risk of death and readmission within one year after discharge. Our study aimed to validate the CODEX index in a large external population of COPD patients with variable durations of follow-up. Additionally, we aimed to recalculate the thresholds of the CODEX index using the cutoffs of variables previously suggested in the 3CIA study (mCODEX). Individual data on 2,755 patients included in the COPD Cohorts Collaborative International Assessment Plus (3CIA+) were explored. A further two cohorts (ESMI AND EGARPOC-2) were added. To validate the CODEX index, the relationship between mortality and the CODEX index was assessed using cumulative/dynamic ROC curves at different follow-up periods, ranging from 3 months up to 10 years. Calibration was performed using univariate and multivariate Cox proportional hazard models and Hosmer-Lemeshow test. A total of 3,321 (87.8% males) patients were included with a mean ± SD age of 66.9 ± 10.5 years, and a median follow-up of 1,064 days (IQR 25-75% 426-1643), totaling 11,190 person-years. The CODEX index was statistically associated with mortality in the short- (≤3 months), medium- (≤1 year) and long-term (10 years), with an area under the curve of 0.72, 0.70 and 0.76, respectively. The mCODEX index performed better in the medium-term (<1 year) than the original CODEX, and similarly in the long-term. In conclusion, CODEX and mCODEX index are good predictors of mortality in patients with COPD, regardless of disease severity or duration of follow-up.

Introduction: A high prevalence of OSA has been observed in asthma populations, with detrimental impact on clinical outcomes., Aim: To determine if CPAP treatment of co-existing OSA improves asthma-related symptoms and quality of life., Methods: Literature review of EMBASE and MEDLINE databases prior to July 2017. Study populations included asthmatics with co-existing OSA treated with CPAP, and ≥1 asthma-related clinical outcome measure., Results: 12 studies; 8 prospective quasi-experimental and 4 observational. Mean CPAP duration; 19.5 (2-100) weeks. Meta-analysis demonstrated significant improvement in mean Asthma Quality of Life Questionnaire scores (AQLQ and mini-AQLQ); 0.59 (95%CI; 0.25, 0.92), p = 0.0006. No significant improvement was demonstrated in forced expiratory volume in 1 s (FEV1)% predicted; 0.32 (95%CI; -2.84, 3.47), p = 0.84. Asthma Control Test/Asthma Control Questionnaire improved in 2 studies, with no improvement in 1 study. 4 studies demonstrated improvement in asthma daytime/night-time symptoms, and 3 studies showed improved asthma severity., Conclusion: Asthmatics with co-existing OSA can experience improved quality of life with CPAP treatment. This effect appears more pronounced in severe OSA or poorly controlled asthma., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background & Aims: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder causing pulmonary and liver disease. The PiZ mutation in AAT (SERPINA1) results in mis-folded AAT protein (Z-AAT) accumulating in hepatocytes, leading to fibrosis and cirrhosis. RNAi-based therapeutics silencing production of hepatic Z-AAT might benefit patients with AATD-associated liver disease. This study evaluated an RNAi therapeutic to silence production of AAT., Methods: Part A of this double-blind first-in-human study randomized 54 healthy volunteers (HVs) into single dose cohorts (two placebo: four active), receiving escalating doses of the investigational agent ARC-AAT from 0.38 to 8.0 mg/kg or placebo. Part B randomized 11 patients with PiZZ (homozygous for Z-AAT) genotype AATD, who received up to 4.0 mg/kg of ARC-AAT or placebo. Patients with baseline FibroScan® >11 kPa or forced expiratory volume in one second (FEV1) <60% were excluded. Assessments included safety, pharmacokinetics, and change in serum AAT concentrations., Results: A total of 36 HVs received ARC-AAT and 18 received placebo (part A). Seven PiZZ individuals received ARC-AAT and four received placebo (part B). A dose response in serum AAT reduction was observed at doses ≥4 mg/kg with similar relative reductions in PiZZ patients and HVs at 4 mg/kg and a maximum reduction of 76.1% (HVs) vs. 78.8% (PiZZ) at this dose. The time it took for serum AAT to return to baseline was similar for HV and PiZZ. There were no notable differences between HV and PiZZ safety parameters. The study was terminated early because of toxicity findings related to the delivery vehicle (ARC-EX1) seen in a non-human primate study., Conclusion: PiZZ patients and HVs responded similarly to ARC-AAT. Deep and durable knockdown of hepatic AAT production based on observed reduction in serum AAT concentrations was demonstrated., Lay Summary: Accumulation of abnormal proteins in the livers of patients with alpha-1 antitrypsin deficiency may lead to decreased liver function and potentially liver failure. Therapeutics targeting the production of these abnormal proteins may be used to prevent or treat liver disease in patients with alpha-1 antitrypsin deficiency., Clinical Trial Registration Number: NCT02363946., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

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), FEV 1 , 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 FEV 1 (p < 0.0001). Total score decline was greater (p < 0.05) for those with accelerated FEV 1 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 FEV 1 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.

Background: External validations and comparisons of prognostic models or scores are a prerequisite for their use in routine clinical care but are lacking in most medical fields including chronic obstructive pulmonary disease (COPD). Our aim was to externally validate and concurrently compare prognostic scores for 3-year all-cause mortality in mostly multimorbid patients with COPD., Methods: We relied on 24 cohort studies of the COPD Cohorts Collaborative International Assessment consortium, corresponding to primary, secondary, and tertiary care in Europe, the Americas, and Japan. These studies include globally 15,762 patients with COPD (1871 deaths and 42,203 person years of follow-up). We used network meta-analysis adapted to multiple score comparison (MSC), following a frequentist two-stage approach; thus, we were able to compare all scores in a single analytical framework accounting for correlations among scores within cohorts. We assessed transitivity, heterogeneity, and inconsistency and provided a performance ranking of the prognostic scores., Results: Depending on data availability, between two and nine prognostic scores could be calculated for each cohort. The BODE score (body mass index, airflow obstruction, dyspnea, and exercise capacity) had a median area under the curve (AUC) of 0.679 [1st quartile-3rd quartile = 0.655-0.733] across cohorts. The ADO score (age, dyspnea, and airflow obstruction) showed the best performance for predicting mortality (difference AUC ADO - AUC BODE = 0.015 [95% confidence interval (CI) = -0.002 to 0.032]; p = 0.08) followed by the updated BODE (AUC BODE updated - AUC BODE = 0.008 [95% CI = -0.005 to +0.022]; p = 0.23). The assumption of transitivity was not violated. Heterogeneity across direct comparisons was small, and we did not identify any local or global inconsistency., Conclusions: Our analyses showed best discriminatory performance for the ADO and updated BODE scores in patients with COPD. A limitation to be addressed in future studies is the extension of MSC network meta-analysis to measures of calibration. MSC network meta-analysis can be applied to prognostic scores in any medical field to identify the best scores, possibly paving the way for stratified medicine, public health, and research.

Background: α1-Antitrypsin deficiency (AATD) predisposes to chronic obstructive pulmonary disease (COPD). In COPD unrelated to AATD, the role of a higher blood eosinophil count in disease and subsequent personalization of therapy has recently received much attention. We sought to investigate this concept in patients with AATD-associated COPD., Objectives: The study aims to evaluate eosinophilia status against outcomes including mortality and FEV1 decline in patients with AATD., Methods: All patients with PiSZ and PiZZ genotypes were identified from the UK AATD registry. The participants were substratified according to inhaled corticosteroid (ICS) use. Blood eosinophil counts were assessed from baseline and annually during follow-up (range 1-18 years). Eosinophilia was defined as a level >0.2 × 109/L, and classified by the frequency of such counts into "always," "intermittent," or "never present." Univariate and multivariate analyses were conducted., Results: In total, 646 participants were included, 53.9% of whom demonstrated intermittent and 7.4% persistent eosinophilia. Survival did not differ according to eosinophilic group (p > 0.05). Those with persistent eosinophilia showed a slower FEV1 decline (p < 0.001). There was no clear association with exacerbation frequency. Patients on ICS at baseline were more likely to be eosinophilic (p = 0.002) and having a lower FEV1 (p < 0.001) and greater pack-year exposure (16.5 vs. 7.8 pack-years, p < 0.001). When the multivariate analyses of FEV1 decline were stratified for baseline ICS use, the association of persistent eosinophilia with slower decline persisted in those on ICS., Conclusions: Blood eosinophil levels persistently >0.2 × 109/L may be an indication for ICS use in PiZZ AATD in order to reduce FEV1 decline., (© 2017 S. Karger AG, Basel.)

Introduction: Noninvasive ventilation (NIV) improves survival among patients with hypercapnic respiratory failure in hospital, but evidence for its use in domiciliary settings is limited. A patient's underlying risk of having an exacerbation may affect any potential benefit that can be gained from domiciliary NIV. This is the first comprehensive systematic review to stratify patients based on a proxy for exacerbation risk: patients in a stable state and those immediately post-exacerbation hospitalization., Methods: A systematic review of nonrandomized and randomized controlled trials (RCTs) was undertaken in order to compare the relative effectiveness of different types of domiciliary NIV and usual care on hospital admissions, mortality, and health-related quality of life. Standard systematic review methods were used for identifying studies (until September 2014), quality appraisal, and synthesis. Data were presented in forest plots and pooled where appropriate using random-effects meta-analysis., Results: Thirty-one studies were included. For stable patients, there was no evidence of a survival benefit from NIV (relative risk [RR] 0.88 [0.55, 1.43], I 2 =60.4%, n=7 RCTs), but there was a possible trend toward fewer hospitalizations (weighted mean difference -0.46 [-1.02, 0.09], I 2 =59.2%, n=5 RCTs) and improved health-related quality of life. For posthospital patients, survival benefit could not be demonstrated within the three RCTs (RR 0.89 [0.53, 1.49], I 2 =25.1%), although there was evidence of benefit from four non-RCTs (RR 0.45 [0.32, 0.65], I 2 =0%). Effects on hospitalizations were inconsistent. Post hoc analyses suggested that NIV-related improvements in hypercapnia were associated with reduced hospital admissions across both populations. Little data were available comparing different types of NIV., Conclusion: The effectiveness of domiciliary NIV remains uncertain; however, some patients may benefit. Further research is required to identify these patients and to explore the relevance of improvements in hypercapnia in influencing clinical outcomes. Optimum time points for commencing domiciliary NIV and equipment settings need to be established.

Background: Many individuals with chronic obstructive pulmonary disease (COPD) remain undiagnosed worldwide. Health-care organisations are implementing case-finding programmes without good evidence of which are the most effective and cost-effective approaches. We assessed the effectiveness and cost-effectiveness of two alternative approaches to targeted case finding for COPD compared with routine practice., Methods: In this cluster-randomised controlled trial, participating general practices in the West Midlands, UK, were randomly assigned (1:1), via a computer-generated block randomisation sequence, to either a targeted case-finding group or a routine care group. Eligible patients were ever-smokers aged 40-79 years without a previously recorded diagnosis of COPD. Patients in the targeted case-finding group were further randomly assigned (1:1) via their household to receive either a screening questionnaire at the general practitioner (GP) consultation (opportunistic) or a screening questionnaire at the GP consultation plus a mailed questionnaire (active). Respondents reporting relevant respiratory symptoms were invited for post-bronchodilator spirometry. Patients, clinicians, and investigators were not masked to allocation, but group allocation was concealed from the researchers who performed the spirometry assessments. Primary outcomes were the percentage of the eligible population diagnosed with COPD within 1 year (defined as post-bronchodilator forced expiratory volume in 1 s [FEV1] to forced vital capacity [FVC] ratio <0·7 in patients with symptoms or a new diagnosis on their GP record) and cost per new COPD diagnosis. Multiple logistic and Poisson regression were used to estimate effect sizes. Costs were obtained from the trial. This trial is registered with ISRCTN, number ISRCTN14930255., Findings: From Aug 10, 2012, to June 22, 2014, 74 818 eligible patients from 54 diverse general practices were randomly assigned and completed the trial. At 1 year, 1278 (4%) cases of COPD were newly detected in 32 789 eligible patients in the targeted case-finding group compared with 337 (1%) cases in 42 029 patients in the routine care group (adjusted odds ratio [OR] 7·45 [95% CI 4·80-11·55], p<0·0001). The percentage of newly detected COPD cases was higher in the active case-finding group (822 [5%] of 15 378) than in the opportunistic case-finding group (370 [2%] of 15 387; adjusted OR 2·34 [2·06-2·66], p<0·0001; adjusted risk difference 2·9 per 100 patients [95% CI 2·3-3·6], p<0·0001). Active case finding was more cost-effective than opportunistic case finding (£333 vs £376 per case detected, respectively)., Interpretation: In this well established primary care system, routine practice identified few new cases of COPD. An active targeted approach to case finding including mailed screening questionnaires before spirometry is a cost-effective way to identify undiagnosed patients and has the potential to improve their health., Funding: National Institute for Health Research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) is characterized by fixed airflow obstruction and accelerated decline of forced expired volume in 1 second (FEV1). Alpha-1-antitrypsin deficiency is a genetic cause of COPD and associated with more rapid decline in lung function, even in some never smokers (NS) but the potential for individualized assessment to reveal differences when compared to group analyses has rarely been considered., Methods: We analyzed decline in post-bronchodilator FEV1 and gas transfer (% predicted) over at least 3 years (mean= 6.11, 95% CI 5.80-6.41) in our unique data set of 482 patients with alpha-1-antitrypsin deficiency (PiZ) to determine individual rates of decline, implications for prognosis, and potential clinical management., Findings: There was a marked variation in individual rates of FEV1 decline from levels consistent with normal aging (observed in 23.5% of patients with established COPD, 57.5% of those without) to those of rapidly declining COPD. Gas transfer did not decline in 12.8% of NS and 20.7% of ex-smokers with established COPD (33.3% and 25.0%, respectively, for those without COPD). There was no correlation between decline in gas transfer and FEV1 for those with COPD, although a weak relationship existed for those without (r=0.218; P<0.025)., Conclusion: These data confirm differing individual rates of lung function decline in alpha-1-antitrypsin deficiency, indicating the importance of comprehensive physiological assessment and a personalized approach to patient management.

In 2013, 16 U.K. hospital trusts participated in a quality improvement programme involving implementation of a community-acquired pneumonia (CAP) care bundle. High-level data were collected on 14,962 patients admitted with CAP; bundle implementation increased from 1% in October 2012 to 20% by September 2013. Analysis of patient-level data on 2118 adults (median age 75.3 years) found that in the bundle-implementation group, significantly more patients received antibiotics within 4 h of admission (adjusted OR 1.52, 95% CI 1.08 to 2.14, p=0.016) and 30-day inpatient mortality was lower (8.8% vs. 13.6%; adjusted OR 0.59, 95% CI 0.37 to 0.95, p=0.03)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Phenotypic differences in physiologic, radiologic, and clinical characteristics are increasingly recognized in COPD. The factors associated with a 1 -antitrypsin deficiency (A1AD)physiologic phenotypes and how they progress with time have yet to be explained., Methods: The study comprised 530 patients with the homozygote Z variant (PiZZ) A1AD; 255 patients had greater than or equal to 3 years of data for longitudinal analysis. Patients were categorized into four groups using lower limits of normal for the carbon monoxide transfer coefficient (K ) and postbronchodilator FEV 1 /FVC ratio. Group comparisons were undertaken for demographic, clinical, physiologic, health status, survival, and CT scan data., Results: Groups with normal lung function or isolated gas transfer defect had the lowest smoking history , least emphysema, and best health status. The group with air flow obstruction (AO) alone had a greater smoking history, more emphysema, and worse health status compared with the normal group. The group with combined AO and gas transfer defect was the worst. The group with AO alone had a faster subsequent decline in K CO than the normal group ( P =.002) and the group with both AO and reduced gas transfer ( P < .001) and was more likely to change groups with time(62% moved to group B). Lower baseline K CO and male sex predicted 89% of the movement to the group with both physiologic abnormalities., Conclusions: There are distinct physiologic phenotypes in A1AD with differing demographic features that relate to progression.

The recognition of α-1-antitrypsin deficiency, its function, and its role in predisposition to the development of severe emphysema was a watershed in our understanding of the pathophysiology of the condition. This led to the concept and development of intravenous replacement therapy used worldwide to protect against lung damage induced by neutrophil elastase. Nevertheless, much remained unknown about the deficiency and its impact, although in recent years the genetic and clinical variations in manifestation have provided new insights into assessing impact, efficacy of therapy, and development of new therapeutic strategies, including gene therapy, and outcome measures, such as biomarkers and computed tomography. The current article reviews this progress over the preceding 50 years., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Alpha 1 antitrypsin deficiency (AATD) is a rare cause of chronic obstructive pulmonary disease. The lung disease is thought to be caused primarily by a lack of effective protection against the harmful effects of neutrophil elastase due to the low AAT levels in the lung. Patients may also develop liver disease due to polymerisation of AAT within hepatocytes. Consequently there has been much research over the years into AAT augmentation therapy in patients with lung disease, initially intravenously, and more recently in inhaled forms. This review article will discuss the role of augmentation therapy in AATD and the current status of recombinant AAT. The potential for other therapeutic strategies, such as blocking polymer formation, enhancing autophagy, gene therapy and stem cell-based treatment, will also be discussed more briefly.

Acute Lung Injury (ALI) and the more severe form Acute Respiratory Distress Syndrome (ARDS) remain a significant cause of morbidity and mortality in the critically ill patient. It is characterised by a severe inflammatory process resulting in diffuse alveolar damage, influx of neutrophils, macrophages and a protein rich exudate in the alveolar spaces caused by endothelial and epithelial injury. Improvements in outcomes are in part due to restrictive fluid management and protective lung ventilation however successful therapeutic strategies remain elusive with promising therapies failing to translate positively in human studies. The evidence for the role of vitamin D in lung disease is growing - deficiency has been associated with impaired pulmonary function, increased incidence of viral and bacterial infections and inflammatory disease including asthma and COPD. Studies have also reported a high prevalence of vitamin D deficiency in the critically ill and an association with adverse outcomes. Although exact mechanisms are yet to be discerned, vitamin D appears to impact on a variety of inflammatory and structural cells within the lung including macrophages, lymphocytes and epithelial cells. To date there are few directly supportive clinical studies in ALI; this review explores the compelling evidence suggesting arole for vitamin D in ALI and the mechanisms by which it could contribute to pathogenesis.

Vitamin D stimulates transcription of antiangiogenic and apoptotic factors that may suppress tumours, while vitamin D binding protein (DBP) may be a biomarker in murine lung cancer models. We sought to ascertain whether the vitamin D axis is altered in lung cancer or influences prognosis. 148 lung cancer patients, 68 other intrathoracic cancer patients and 33 noncancer controls were studied for up to 5 yrs. Circulating DBP and vitamin D levels were compared between groups and their effect on survival assessed by Cox regression analysis. Expression of DBP and vitamin D receptor (VDR) was examined in lung cancer cell lines and in normal and tumour lung tissue by Western blot and immunohistochemistry. Low serum DBP levels predicted lung cancer-specific death (p=0.04), and DBP was poorly expressed in lung cancer cells on Western blot and immunohistochemistry. Vitamin D did not predict cancer survival and VDR expression was variable in tumours. Preservation of serum DBP is a significant independent factor associated with better cancer outcome in operated lung cancer patients. Given the established role of DBP in macrophage activation and clearance of abnormal cells, further study on its involvement in lung cancer is merited.