Publications by authors named "Robert Stockley"

171 Publications

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

Radiology 2021 Feb 16:203531. Epub 2021 Feb 16.

From the Division of Pulmonary and Critical Care Medicine, Department of Medicine (S.Y.A., A.A.D., S.E.M., F.N.R., C.L.P., G.R.W.), Applied Chest Imaging Laboratory (S.Y.A., R.S.J.E., A.A.D., S.E.M., F.N.R., C.L.P., G.V.S.F., G.R.W.), and Department of Radiology (R.S.J.E., G.V.S.F.), Brigham and Women's Hospital, 75 Francis St, PBB, CA-3, Boston, MA 02130; Departments of Biomedical Engineering and Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, Wis (S.B.F.); COPD Foundation, Washington, DC (R.T.S., D.M.); Lung Investigation Unit, Medicine, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, England (R.A.S.); Respiratory and Inflammation Therapy Area, Clinical Development, AstraZeneca, Mölndal, Sweden (L.H.N.); Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Nebraska Medical Center, Omaha, Neb (S.R.); Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Mich (M.K.H.); Department of Radiology, National Jewish Health, Denver, Colo (S.M.H., D.A.L.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Department of Medicine, University of Pittsburgh, Pittsburgh, Pa (F.C.S.).

Background The relationship between emphysema progression and long-term outcomes is unclear. Purpose To determine the relationship between emphysema progression at CT and mortality among participants with emphysema. Materials and Methods In a secondary analysis of two prospective observational studies, COPDGene (, NCT00608764) and Evaluation of Chronic Obstructive Pulmonary Disease Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE; , NCT00292552), emphysema was measured at CT at two points by using the volume-adjusted lung density at the 15th percentile of the lung density histogram (hereafter, lung density perc15) method. The association between emphysema progression rate and all-cause mortality was analyzed by using Cox regression adjusted for ethnicity, sex, baseline age, pack-years, and lung density, baseline and change in smoking status, forced expiratory volume in 1 second, and 6-minute walk distance. In COPDGene, respiratory mortality was analyzed by using the Fine and Gray method. Results A total of 5143 participants (2613 men [51%]; mean age, 60 years ± 9 [standard deviation]) in COPDGene and 1549 participants (973 men [63%]; mean age, 62 years ± 8) in ECLIPSE were evaluated, of which 2097 (40.8%) and 1179 (76.1%) had emphysema, respectively. Baseline imaging was performed between January 2008 and December 2010 for COPDGene and January 2006 and August 2007 for ECLIPSE. Follow-up imaging was performed after 5.5 years ± 0.6 in COPDGene and 3.0 years ± 0.2 in ECLIPSE, and mortality was assessed over the ensuing 5 years in both. For every 1 g/L per year faster rate of decline in lung density perc15, all-cause mortality increased by 8% in COPDGene (hazard ratio [HR], 1.08; 95% CI: 1.01, 1.16; = .03) and 6% in ECLIPSE (HR, 1.06; 95% CI: 1.00, 1.13; = .045). In COPDGene, respiratory mortality increased by 22% (HR, 1.22; 95% CI: 1.13, 1.31; < .001) for the same increase in the rate of change in lung density perc15. Conclusion In ever-smokers with emphysema, emphysema progression at CT was associated with increased all-cause and respiratory mortality. © RSNA, 2021 See also the editorial by Lee and Park in this issue.
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http://dx.doi.org/10.1148/radiol.2021203531DOI Listing
February 2021

COPD frequent exacerbators: time for the recycle bin?

Eur Respir J 2021 Feb 11;57(2). Epub 2021 Feb 11.

Lung Investigation Unit, Queen Elizabeth Hospital Birmingham, Edgbaston, UK

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http://dx.doi.org/10.1183/13993003.03758-2020DOI Listing
February 2021

Improving the Lives of Patients with Alpha-1 Antitrypsin Deficiency.

Int J Chron Obstruct Pulmon Dis 2020 10;15:3313-3322. Epub 2020 Dec 10.

University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, UK.

Alpha-1 Antitrypsin Deficiency (AATD) is a rare genetic condition that predisposes patients to lung and liver disease and is often underdiagnosed due to incomplete diagnosis of chronic obstructive pulmonary disease (COPD) and asthma. Improvements in physician awareness have been made, but better strategies for both diagnosis and management are still required. The only current disease-modifying therapy for AATD is the infusion of the missing Alpha-1 Antitrypsin (AAT) protein, which can slow progression of emphysema. However, AAT treatment can impact patient freedom and quality of life due to the need for weekly intravenous infusions. A symposium was held to discuss patient-centric aspects of care that have impact on the lives of patients with AATD, including exacerbations of their lung disease, self-administration of intravenous AAT therapy and pulmonary rehabilitation. Intravenous self-infusion of drugs is an established treatment strategy for patients with a variety of conditions and can improve patient quality of life, freedom and mental well-being. Experience from these areas show that patients typically manage their treatment well and without complications. When applied to AATD, training patients to self-infuse therapy can be successful, but formal guidelines would be beneficial. In addition to pharmacological intervention, individualized pulmonary rehabilitation, exercise and educational programs can encourage health-enhancing patient behavior and further improve patient quality of life. However, differences in skeletal muscle adaptations to pulmonary rehabilitation exercise regimens have been observed between patients with AATD and non-AATD COPD, highlighting the need to develop training programs specifically designed for patients with AATD.
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http://dx.doi.org/10.2147/COPD.S276773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735792PMC
December 2020

Monocytes and Macrophages in Alpha-1 Antitrypsin Deficiency.

Int J Chron Obstruct Pulmon Dis 2020 3;15:3183-3192. Epub 2020 Dec 3.

Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.

Alpha-1 antitrypsin deficiency (AATD) is a genetic condition characterised by low circulating levels of alpha-1 antitrypsin (AAT), a serine proteinase inhibitor. The most common deficiency variants are the S and Z mutations, which cause the accumulation of misfolded AAT in hepatocytes resulting in endoplasmic reticular stress and insufficient release of AAT into the circulation (<11μmol/L). This leads to liver disease, as well as an increased risk of emphysema due to unopposed proteolytic activity of neutrophil-derived serine proteinases in the lungs. AATD has been traditionally viewed as an inflammatory disorder caused directly by a proteinase-antiproteinase imbalance in the lung, but increasing evidence suggests that low AAT levels may affect other cellular functions. Recently, AAT polymers have been identified in both monocytes and macrophages from AATD patients and evidence is building that these cells may also play a role in the development of AATD lung disease. Alveolar macrophages are phagocytic cells that are important in the lung immune response but are also implicated in driving inflammation. This review explores the potential implications of monocyte and macrophage involvement in non-liver AAT synthesis and the pathophysiology of AATD lung disease.
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http://dx.doi.org/10.2147/COPD.S276792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725100PMC
December 2020

From GOLD 0 to Pre-COPD.

Am J Respir Crit Care Med 2021 02;203(4):414-423

Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, member of the German Center for Lung Research (DZL), Philipps-University, Marburg, Germany.

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http://dx.doi.org/10.1164/rccm.202008-3328PPDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885837PMC
February 2021

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.

BMJ Open 2020 06 30;10(6):e036045. Epub 2020 Jun 30.

University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, Birmingham, UK

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.
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http://dx.doi.org/10.1136/bmjopen-2019-036045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328802PMC
June 2020

The clinical and inflammatory relationships between periodontitis and chronic obstructive pulmonary disease.

J Clin Periodontol 2020 09 9;47(9):1040-1052. Epub 2020 Jul 9.

Respiratory Medicine, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.

Aim: To investigate associations between periodontitis and chronic obstructive pulmonary disease (COPD) with and without alpha-1 antitrypsin deficiency (AATD), including neutrophil functions implicated in tissue damage.

Methods: The presence and severity of periodontitis (using two international criteria) and lung disease were assessed in 156 COPD patients with and without AATD accounting for common confounding factors. Saliva and systemic inflammatory markers were measured by ELISA together with neutrophil migration.

Results: COPD and AATD patients exhibited higher prevalence of periodontitis (COPD 95%; AATD 88%) than reported in unselected community-dwelling populations even when risk factors (age, smoking history, socio-economic status and dental habits) were considered. Periodontitis severity associated with lung disease severity (AATD, periodontitis versus no periodontitis; FEV1 = 56% versus 99% predicted; TLCO = 59% versus 81% predicted, p < .0001 for both). Neutrophil migratory accuracy declined in stage II-IV periodontitis patients with COPD or AATD compared to COPD or AATD with no or stage I periodontitis. Improved dental habits appeared to be associated with a reduction in exacerbation frequency in COPD.

Conclusion: The results support shared pathophysiology between periodontitis and COPD, especially when associated with AATD. This may reflect an amplification of neutrophilic inflammation and altered neutrophil functions, already described in periodontitis, COPD and AATD.
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http://dx.doi.org/10.1111/jcpe.13334DOI Listing
September 2020

An overview of exacerbations of chronic obstructive pulmonary disease: Can tests of small airways' function guide diagnosis and management?

Ann Thorac Med 2020 Apr-Jun;15(2):54-63. Epub 2020 Apr 3.

Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.

Chronic obstructive pulmonary disease (COPD) is common and debilitating. Most patients with COPD experience intermittent, acute deterioration in symptoms which require additional therapy, termed exacerbations. Exacerbations are prevalent in COPD and are associated with poor clinical outcomes including death, a faster decline in lung health, and a reduced quality of life. Current guidelines highlight the need to treat exacerbations promptly and then mitigate future risk. However, exacerbations are self-reported, difficult to diagnose and are treated with pharmacological therapies which have largely been unchanged over 30 years. Recent research has highlighted how exacerbations vary in their underlying cause, with specific bacteria, viruses, and cell types implicated. This variation offers the opportunity for new targeted therapies, but to develop these new therapies requires sensitive tools to reliably identify the cause, the start, and end of an exacerbation and assess the response to treatment. Currently, COPD is diagnosed and monitored using spirometric measures, principally the forced expiratory volume in 1 s and forced vital capacity, but these tests alone cannot reliably diagnose an exacerbation. Measures of small airways' function appear to be an early marker of COPD, and some studies have suggested that these tests might also provide physiological biomarkers for exacerbations. In this review, we will discuss how exacerbations of COPD are currently defined, stratified, monitored, and treated and review the current literature to determine if tests of small airways' function might improve diagnostic accuracy or the assessment of response to treatment.
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http://dx.doi.org/10.4103/atm.ATM_323_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259399PMC
April 2020

Alpha-1 Antitrypsin Deficiency: Have We Got the Right Proteinase?

Chronic Obstr Pulm Dis 2020 Jul;7(3):163-171

Lung Investigation Unit, University Hospitals, Birmingham National Health Service Foundation Trust, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom.

Alpha-1 antitrypsin deficiency (AATD) has traditionally been associated with the development of early onset panlobular emphysema thought to reflect the direct interstitial damage caused by neutrophil elastase. Since this enzyme is highly sensitive to irreversible inhibition by alpha-1 antitrypsin (AAT), the logic of intravenous augmentation therapy has remained unquestioned and efficacy is supported by both observational studies and formal clinical trials. However, evidence suggests that although AAT augmentation modulates the progression of emphysema, it only slows it down. This raises the issue of whether our long-held beliefs of the cause of the susceptibility to develop emphysema in deficient individuals are correct. There are several aspects of our understanding of the disease that might benefit from a radical departure from traditional thought. This review addresses these concepts and alternative pathways that may be central to progression of emphysema.
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http://dx.doi.org/10.15326/jcopdf.7.3.2019.0151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857712PMC
July 2020

Alpha-1 Antitrypsin Deficiency: The Learning Goes On.

Am J Respir Crit Care Med 2020 07;202(1):6-7

Department of Sleep and Lung FunctionQueen Elizabeth HospitalBirmingham, United Kingdom.

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http://dx.doi.org/10.1164/rccm.202004-0922EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328316PMC
July 2020

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

Eur Respir J 2020 06 18;55(6). Epub 2020 Jun 18.

Lung Investigation Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

α-Antitrypsin deficiency (AATD), characterised by reduced levels or functionality of α-antitrypsin (AAT), is a significantly underdiagnosed genetic condition that predisposes individuals to lung and liver disease. Most of the available data on AATD are based on the most common, severe deficiency genotype (PI*ZZ); therefore, treatment and monitoring requirements for individuals with the PI*SZ genotype, which is associated with a less severe AATD, are not as clear. Recent genetic data suggest the PI*SZ genotype may be significantly more prevalent than currently thought, due in part to less frequent identification in the clinic and less frequent reporting in registries. Intravenous AAT therapy, the only specific treatment for patients with AATD, has been shown to slow disease progression in PI*ZZ individuals; however, there is no specific evidence for AAT therapy in PI*SZ individuals, and it remains unclear whether AAT therapy should be considered in these patients. This narrative review evaluates the available data on the PI*SZ genotype, including genetic prevalence, the age of diagnosis and development of respiratory symptoms compared with PI*ZZ individuals, and the impact of factors such as index non-index identification and smoking history. In addition, the relevance of the putative 11 µM "protective threshold" for AAT therapy and the risk of liver disease in PI*SZ individuals is explored. The purpose of this review is to identify open research questions in this area, with the aim of optimising the future identification and management of PI*SZ individuals.
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http://dx.doi.org/10.1183/13993003.02410-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301289PMC
June 2020

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

ERJ Open Res 2020 Jan 2;6(1). Epub 2020 Mar 2.

Pneumology Dept, Hospital Universitari Vall d'Hebron/Vall d'Hebron Research Institute (VHIR), CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain.

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) 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.
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http://dx.doi.org/10.1183/23120541.00181-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049712PMC
January 2020

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

Eur Respir J 2019 11 21;54(5). Epub 2019 Nov 21.

Queen Elizabeth Hospital, Birmingham, UK.

Patients with inherited α1-antitrypsin (AAT) deficiency (ZZ-AATD) and severe chronic obstructive pulmonary disease (COPD) frequently experience exacerbations. We postulated that inhalation of nebulised AAT would be an effective treatment.We randomly assigned 168 patients to receive twice-daily inhalations of 80 mg AAT solution or placebo for 50 weeks. Patients used an electronic diary to capture exacerbations. The primary endpoint was time from randomisation to the first event-based exacerbation. Secondary endpoints included change in the nature of the exacerbation as defined by the Anthonisen criteria. Safety was also assessed.Time to first moderate or severe exacerbation was a median of 112 days (interquartile range (IQR) 40-211 days) for AAT and 140 days (IQR 72-142 days) for placebo (p=0.0952). The mean yearly rate of all exacerbations was 3.12 in the AAT-treated group and 2.67 in the placebo group (p=0.31). More patients receiving AAT reported treatment-related treatment-emergent adverse events compared to placebo (57.5% 46.9%, respectively) and they were more likely to withdraw from the study. After the first year of the study, when modifications to the handling of the nebuliser were introduced, the rate of safety events in the AAT-treated group dropped to that of the placebo group.We conclude that in AATD patients with severe COPD and frequent exacerbations, AAT inhalation for 50 weeks showed no effect on time to first exacerbation but may have changed the pattern of the episodes.
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http://dx.doi.org/10.1183/13993003.00673-2019DOI Listing
November 2019

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

ERJ Open Res 2019 Jul 5;5(3). Epub 2019 Aug 5.

University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, UK.

α-Antitrypsin (α-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 α-AT deficiency. An ELISA was developed for the specific PR3 fibrinogen cleavage site Aα-Val. 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-Val was greater than the NE footprint in all cohorts, consistent with differential activity. Values were highest in the PiZZ α-AT-deficient patients and correlated with the NE marker Aα-Val, but were ∼17 times higher than for the NE footprint, consistent with a greater potential contribution to lung damage. Aα-Val was related cross-sectionally to the severity of lung disease (forced expiratory volume in 1 s % pred: r= -0.284; p<0.001) and was sensitive to augmentation therapy, falling from 287.2 to 48.6 nM (p<0.001). An plasma footprint of PR3 activity is present in greater quantities than an NE footprint in patients with α-AT deficiency, is sensitive to augmentation therapy and represents a likely biomarker for dose-ranging studies.
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http://dx.doi.org/10.1183/23120541.00095-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680069PMC
July 2019

Neutrophil phenotypes in chronic lung disease.

Expert Rev Respir Med 2019 10 21;13(10):951-967. Epub 2019 Aug 21.

Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham , Birmingham , UK.

: Neutrophils are the most abundant inflammatory cells in the lungs of patients with chronic lung diseases, especially COPD, yet despite this, patients often experience repeated chest infections. Neutrophil function may be altered in disease, but the reasons are unclear. In chronic disease, sequential pro-inflammatory and pro-repair responses appear distorted. As understanding of neutrophil heterogeneity has expanded, it is suggested that different neutrophil phenotypes may impact on health and disease. In this review, the definition of cellular phenotype, the implication of neutrophil surface markers and functions in chronic lung disease and the complex influences of external, local and genetic factors on these changes are discussed. Literature was accessed up to the 19 July 2019 using: PubMed, US National Library of Medicine National Institutes of Health and the National Centre for Biotechnology Information. : As more is learned about neutrophils, the further we step from the classical view of neutrophils being unrefined killing machines to highly complex and finely tuned cells. Future therapeutics may aim to normalize neutrophil function, but to achieve this, knowledge of phenotypes in humans and how these relate to observed pathology and disease processes is required.
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http://dx.doi.org/10.1080/17476348.2019.1654377DOI Listing
October 2019

Model-based evaluation of the long-term cost-effectiveness of systematic case-finding for COPD in primary care.

Thorax 2019 08 8;74(8):730-739. Epub 2019 Jul 8.

Health Economics Unit, University of Birmingham, Birmingham, UK

Introduction: 'One-off' systematic case-finding for COPD using a respiratory screening questionnaire is more effective and cost-effective than routine care at identifying new cases. However, it is not known whether early diagnosis and treatment is beneficial in the longer term. We estimated the long-term cost-effectiveness of a regular case-finding programme in primary care.

Methods: A Markov decision analytic model was developed to compare the cost-effectiveness of a 3-yearly systematic case-finding programme targeted to ever smokers aged ≥50 years with the current routine diagnostic process in UK primary care. Patient-level data on case-finding pathways was obtained from a large randomised controlled trial. Information on the natural history of COPD and treatment effects was obtained from a linked COPD cohort, UK primary care database and published literature. The discounted lifetime cost per quality-adjusted life-year (QALY) gained was calculated from a health service perspective.

Results: The incremental cost-effectiveness ratio of systematic case-finding versus current care was £16 596 per additional QALY gained, with a 78% probability of cost-effectiveness at a £20 000 per QALY willingness-to-pay threshold. The base case result was robust to multiple one-way sensitivity analyses. The main drivers were response rate to the initial screening questionnaire and attendance rate for the confirmatory spirometry test.

Discussion: Regular systematic case-finding for COPD using a screening questionnaire in primary care is likely to be cost-effective in the long-term despite uncertainties in treatment effectiveness. Further knowledge of the natural history of case-found patients and the effectiveness of their management will improve confidence to implement such an approach.
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http://dx.doi.org/10.1136/thoraxjnl-2018-212148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703126PMC
August 2019

Alpha-1 Antitrypsin Deficiency: A Predisposing Factor for the Development of Pulmonary Langerhans Cell Histiocytosis.

Chronic Obstr Pulm Dis 2019 Jul;6(3):206-209

University Birmingham NHS Foundation Trust, Birmingham, United Kingdom.

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http://dx.doi.org/10.15326/jcopdf.6.3.2019.0129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872215PMC
July 2019

Alpha-1 Antitrypsin Deficiency and Accelerated Aging: A New Model for an Old Disease?

Drugs Aging 2019 09;36(9):823-840

Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham, B15 2GW, UK.

Alpha-1 antitrypsin (AAT) protects the lung by inhibiting neutrophil proteinases, but AAT has many other non-proteolytic functions that are anti-inflammatory, antiviral and homeostatic. Approximately 1 in 1600 to 1 in 5000 people have the homozygous Z mutation, which causes AAT misfolding, accumulation in (predominantly) liver cells and low circulating levels of AAT, leading to AAT deficiency (AATD). AATD is classically a disease of neutrophilic inflammation, with an aggressive and damaging innate immune response contributing to emphysema and other pathologies. AATD is one of the most common genetic disorders but considerably under-recognised. Most patients are diagnosed later in life, by which time they may have accumulated significant lung, liver and multisystem damage. Disease presentation is heterogeneous and not fully explained by deficiency levels alone or exposure to cigarette smoking. This suggests other factors influence AATD-associated pathological processes. Aging itself is associated with organ dysfunction, including emphysema and airflow obstruction, inflammation, altered immune cell responses (termed immunosenescence) and a loss of proteostasis. Many of these processes are present in AATD but at an earlier age and more advanced stage compared with chronological aging alone. Augmentation therapy does not completely abrogate the manifold disease processes present in AATD. New approaches are needed. There is emerging evidence that both age- and AATD-related disease processes are amenable to correction by targeting proteostasis, autophagy, immunosenescence and epigenetic factors. This review explores the impact of the aging process on AATD presentation and discusses novel therapeutic strategies to mitigate low levels of AAT or misfolded AAT in an aging host.
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http://dx.doi.org/10.1007/s40266-019-00684-7DOI Listing
September 2019

Corporate Memory and Rediscovering the Wheel.

Am J Respir Crit Care Med 2019 Jul;200(1):2-4

1 University Hospitals Birmingham NHS Foundation Trust Queen Elizabeth Hospital Birmingham Birmingham, United Kingdom.

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http://dx.doi.org/10.1164/rccm.201901-0066EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603050PMC
July 2019

Getting stuck or choosing to stay? Neutrophil transit times in the lung in acute inflammation and COPD.

Thorax 2019 07 16;74(7):631-632. Epub 2019 May 16.

Respiratory Medicine, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.

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http://dx.doi.org/10.1136/thoraxjnl-2018-213000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585287PMC
July 2019

The Biological Effects of Double-Dose Alpha-1 Antitrypsin Augmentation Therapy. A Pilot Clinical Trial.

Am J Respir Crit Care Med 2019 08;200(3):318-326

6Lung Investigation Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom.

Augmentation therapy with intravenous AAT (alpha-1 antitrypsin) is the only specific therapy for individuals with pulmonary disease from AAT deficiency (AATD). The recommended standard dose (SD; 60 mg/kg/wk) elevates AAT trough serum levels to around 50% of normal; however, outside of slowing emphysema progression, its effects in other clinical outcomes have not been rigorously proven. To evaluate the biological effects of normalizing AAT trough levels with double-dose (DD) therapy (120 mg/kg/wk) in subjects with AATD already receiving SD therapy. Clinically stable subjects were evaluated after 4 weeks of SD therapy, followed by 4 weeks of DD therapy, and 4 weeks after return to SD therapy. At the end of each phase, BAL fluid (BALF) and plasma samples were obtained. DD therapy increased trough AAT levels to normal and, compared with SD therapy, reduced serine protease activity in BALF (elastase and cathepsin G), plasma elastase footprint (Aα-Val), and markers of elastin degradation (desmosine/isodesmosine) in BALF. DD therapy also further downregulated BALF ILs and cytokines including Jak-STAT (Janus kinases-signal transducer and activator of transcription proteins), TNFα (tumor necrosis factor-α), and T-cell receptor signaling pathways, cytokines involved in macrophage migration, eosinophil recruitment, humoral and adaptive immunity, neutrophil activation, and cachexia. On restarting SD after DD treatment, a possible carryover effect was seen for several biological markers. Subjects with AATD on SD augmentation therapy still exhibit inflammation, protease activity, and elastin degradation that can be further improved by normalizing AAT levels. Higher AAT dosing than currently recommended may lead to enhanced clinical benefits and should be explored further.Clinical trial registered with www.clinicaltrials.gov (NCT01669421).
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http://dx.doi.org/10.1164/rccm.201901-0010OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680306PMC
August 2019

Reply to Pouwels : Confounding Factors Affecting sRAGE as a Biomarker for Chronic Obstructive Pulmonary Disease.

Am J Respir Crit Care Med 2019 07;200(1):114-115

4 Manchester University NHS Foundation Hospital Trust Manchester, United Kingdom.

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http://dx.doi.org/10.1164/rccm.201903-0573LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603060PMC
July 2019

Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019.

Eur Respir J 2019 05 18;53(5). Epub 2019 May 18.

Dept of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps University Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany.

Precision medicine is a patient-specific approach that integrates all relevant clinical, genetic and biological information in order to optimise the therapeutic benefit relative to the possibility of side-effects for each individual. Recent clinical trials have shown that higher blood eosinophil counts are associated with a greater efficacy of inhaled corticosteroids (ICSs) in chronic obstructive pulmonary disease (COPD) patients. Blood eosinophil counts are a biomarker with potential to be used in clinical practice, to help target ICS treatment with more precision in COPD patients with a history of exacerbations despite appropriate bronchodilator treatment.The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 pharmacological treatment algorithms, based on the ABCD assessment, can be applied relatively easily to treatment-naive individuals at initial presentation. However, their use is more problematic during follow-up in patients who are already on maintenance treatment. There is a need for a different system to guide COPD pharmacological management during follow-up.Recent large randomised controlled trials have provided important new information concerning the therapeutic effects of ICSs and long-acting bronchodilators on exacerbations. The new evidence regarding blood eosinophils and inhaled treatments, and the need to distinguish between initial and follow-up pharmacological management, led to changes in the GOLD pharmacological treatment recommendations. This article explains the evidence and rationale for the GOLD 2019 pharmacological treatment recommendations.
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http://dx.doi.org/10.1183/13993003.00164-2019DOI Listing
May 2019

The European Alpha-1 Research Collaboration (EARCO): a new ERS Clinical Research Collaboration to promote research in alpha-1 antitrypsin deficiency.

Eur Respir J 2019 02 14;53(2). Epub 2019 Feb 14.

Dept of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre Giessen and Marburg, Philipps-University, Member of the German Centre for Lung Research (DZL), Marburg, Germany.

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http://dx.doi.org/10.1183/13993003.00138-2019DOI Listing
February 2019

Chronic Obstructive Pulmonary Disease Biomarkers and Their Interpretation.

Am J Respir Crit Care Med 2019 05;199(10):1195-1204

4 Medicines Evaluation Unit, University of Manchester, Manchester University NHS Foundation Hospital Trust, Manchester, United Kingdom.

The pathology and impact of chronic obstructive pulmonary disease (COPD) results from an abnormal inflammatory process resulting in tissue damage with ineffective repair in response to toxic inhalants (especially cigarette smoke). Identification of mechanisms provides the opportunity to develop new therapies and a personalized approach to management. The collection of multiple genetic and detailed biochemical data from small and large patient cohorts has led to an explosion of studies investigating biomarkers to achieve these aims. Despite widespread enthusiasm and many statistically significant associations, the interpretation of COPD biomarker results requires thought and leaves many questions unanswered. The present review assesses the importance of these associations, whether they represent cause or effect, reflect disease severity or activity, the complexity of the pathway to the final pathogenic and hence interventional step, and problems with interpreting cross-sectional studies without knowing individual disease trajectories. The complexity of biomarker specificity without sufficient clinical phenotype and endotype information contributes to problems of interpretation. A strategic change is needed to develop useful COPD biomarkers; this includes focusing on endotype biomarkers within specific clinical phenotypes, biomarkers in early COPD, exacerbation subtype biomarkers, and biomarkers to predict or measure drug effects.
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http://dx.doi.org/10.1164/rccm.201810-1860SODOI Listing
May 2019

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

Respir Res 2018 Sep 20;19(1):180. Epub 2018 Sep 20.

University Hospital Birmingham NHS Foundation Trust, Edgbaston, Birmingham, B15 2GW, UK.

Chronic Obstructive Pulmonary Disease (COPD) is a common, multifactorial lung disease which results in significant impairment of patients' health and a large impact on society and health care burden. It is believed to be the result of prolonged, destructive neutrophilic inflammation which results in progressive damage to lung structures. During this process, large quantities of neutrophil serine proteinases (NSPs) are released which initiate the damage and contribute towards driving a persistent inflammatory state.Neutrophil elastase has long been considered the key NSP involved in the pathophysiology of COPD. However, in recent years, a significant role for Proteinase 3 (PR3) in disease development has emerged, both in COPD and other chronic inflammatory conditions. Therefore, there is a need to investigate the importance of PR3 in disease development and hence its potential as a therapeutic target. Research into PR3 has largely been confined to its role as an autoantigen, but PR3 is involved in triggering inflammatory pathways, disrupting cellular signalling, degrading key structural proteins, and pathogen response.This review summarises what is presently known about PR3, explores its involvement particularly in the development of COPD, and indicates areas requiring further investigation.
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http://dx.doi.org/10.1186/s12931-018-0883-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149181PMC
September 2018

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

Respir Res 2018 07 20;19(1):137. Epub 2018 Jul 20.

Institute of Applied Health Research, University of Birmingham, Birmingham, B15 2TT, UK.

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, 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 (p < 0.0001). Total score decline was greater (p < 0.05) for those with accelerated FEV 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 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.
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http://dx.doi.org/10.1186/s12931-018-0844-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053712PMC
July 2018

Pharmacological treatment of COPD: the devil is always in the detail.

Eur Respir J 2018 04 19;51(4). Epub 2018 Apr 19.

Hospital Clínic, Universitat de Barcelona, Ciberes, Barcelona, Spain.

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http://dx.doi.org/10.1183/13993003.00263-2018DOI Listing
April 2018

ICS Use May Modify FEV1 Decline in α1-Antitrypsin Deficiency Patients with Relatively High Blood Eosinophils.

Respiration 2018;95(2):114-121. Epub 2017 Dec 18.

Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom.

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.
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http://dx.doi.org/10.1159/000481867DOI Listing
October 2018