Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ).

BACKGROUND & AIMS: α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. METHODS: Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. RESULTS: Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. CONCLUSIONS: The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

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.

Early respiratory diagnosis: benefits of enhanced lung function assessment.

INTRODUCTION: The National Health Service for England Long Term Plan identifies respiratory disease as one of its priority workstreams. To assist with earlier and more accurate diagnosis of lung disease they recommend improvement in delivery of quality-assured spirometry. However, there is a likelihood that patients will present with abnormal gas exchange when spirometry results are normal and therefore there will be a proportion of patients whose time to diagnosis is still protracted. We wished to determine the incidence rate of this occurring within our Trust. METHODS: A retrospective review of all patients attending the lung function laboratory for their first pulmonary function assessment from June 2006 to December 2020 was undertaken. Forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) >-1.64 standardised residual (SR) was used to confirm no obstructive lung function abnormality and FVC >-1.64 SR to confirm no suggestion of a restrictive lung function abnormality. Lung gas transfer for carbon monoxide (TLCO) and transfer coefficient of the lung for carbon monoxide (KCO) <-1.64 SR confirmed the presence of a gas exchange abnormality. Spirometry and gas transfer reference values generated by the Global Lung Initiative were used to determine normality. RESULTS: Of 12 835 eligible first visits with normal FEV1/FVC and FVC, 4856 (37.8%) were identified as having an abnormally low TLCO and 3302 (25.7%) presenting with an abnormally low KCO. Of 3494 with FEV1/FVC SR <-1.64, 3316 also had a ratio of <0.70, meaning 178 (5%) of patients in this cohort would have been misclassified as having obstructive lung disease using the 0.70 cut-off recommended by the Global Initiative for Chronic Obstructive Lung Disease for diagnosing obstructive lung disease. DISCUSSION: In conclusion, to assist with ensuring more accurate and timely diagnosis of lung disease and enhance patients' diagnostic pathway, we recommend the performance of lung gas transfer measurements alongside spirometry in all healthcare settings. To assess and monitor gas transfer at the earliest opportunity we recommend this is implemented into new models being developed within community hubs. This will increase the identification of lung function abnormalities and provide patients with a definitive diagnosis earlier.

Communicating uncertainty: contrasting the communication experiences of patients with advanced COPD and incurable lung cancer.

BACKGROUND: 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. OBJECTIVE: This study sought to identify factors that impact communication and support and recommend ways to improve patients' understanding of living with life-threatening illness. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Relationship of CT densitometry to lung physiological parameters and health status in alpha-1 antitrypsin deficiency: initial report of a centralised database of the NIHR rare diseases translational research collaborative.

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<0.001) and carbon monoxide gas transfer (p<0.01). Density also correlated with subjective measures of quality of life (p=0.02). CONCLUSIONS: Establishment of the network for data collection and its transfer was highly successful facilitating future collaboration for the study of this rare disease and its management. CT densitometry correlated well with the objective clinical features of the disease supporting its role as the specific marker of the associated emphysema and its severity. Correlations with subjective measures of health, however, were generally weak indicating other factors play a role.

Protocol for the EARCO Registry: a pan-European observational study in patients with α1-antitrypsin deficiency.

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 <11 µM (50 mg·dL-1) and/or a proteinase inhibitor genotype ZZ, SZ or compound heterozygotes or homozygotes of other rare deficient variants. Assessments at baseline and during the yearly follow-up visits include lung function testing (spirometry, body plethysmography and diffusing capacity of the lung), exercise capacity, blood tests and questionnaires (symptoms, quality of life and physical activity). To ensure correct data collection, there will be designated investigator staff to document the data in the case report form. All data will be reviewed by the EARCO database manager. SUMMARY: The EARCO Registry aims to understand the natural history and prognosis of AATD better with the goal to create and validate prognostic tools to support medical decision-making.

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

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

Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation.

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.

Lung function improvements in emphysema following pneumonia.

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.

The role of a multidisciplinary severe chronic obstructive pulmonary disease hyperinflation service in patient selection for lung volume reduction.

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.

Trends of testing for and diagnosis of α1-antitrypsin deficiency in the UK: more testing is needed.

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 p<0.05).Despite 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.

Living with COPD: the struggle for breath and for lung volume reduction therapies.

Access to lung volume reduction for advanced emphysema http://ow.ly/Iqru30jbvbE.

British Thoracic Society Quality Standards for acute non-invasive ventilation in adults.

INTRODUCTION: The 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. METHODS: Development 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. RESULTS: 6 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. CONCLUSION: BTS 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.

Do patients and carers agree on symptom burden in advanced COPD?

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.

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

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

Associations between the psychological health of patients and carers in advanced COPD.

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.

Alpha1-antitrypsin binds hemin and prevents oxidative activation of human neutrophils: putative pathophysiological significance.

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.

Six key topics informal carers of patients with breathlessness in advanced disease want to learn about and why: MRC phase I study to inform an educational intervention.

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. 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. 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. 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.