R A Stockley

University of Birmingham, Birmingham, England, United Kingdom

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Publications (247)1712.22 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The PiSZ genotype results in less severe deficiency of alpha-1 antitrypsin (AAT) than PiZZ. Less is known about phenotypic and prognostic features. We studied 699 PiZZ, 126 PiSZ and 316 PiMM patients. All AAT deficiency (AATD) patients were augmentation naive. PiSZ were compared with PiZZ patients for clinical phenotype at baseline including CT findings, smoke exposure, progression of lung disease and survival. Similarly, PiSZ patients diagnosed as a result of investigation for possible lung disease (lung index cases) were compared with PiMM. Multivariable analytical techniques and matching (PiSZ to PiZZ) were employed to account for demographic differences. Pack-years smoked and FEV1 exhibited a negative correlation in PiSZ and ZZ patients (both r=-0.43), with emphysema and COPD occurring more commonly in PiZZ patients at <20 pack-year exposure. In multivariable analyses, PiSZ patients were less likely to have emphysema (p<0.01) and had better survival than PiZZ (p=0.017), but lung function decline did not differ significantly. 42% of PiSZ patients had upper-zone-dominant emphysema on CT scan. Analyses of AAT level confirmed a critical threshold at 11 μM, particularly with regard to phenotypes classical of PiZZ AATD.Significant baseline differences suggested that PiSZ had presented earlier to health services than PiMM. Once this was accounted for, risk of emphysema did not differ between PiSZ and PiMM although survival was lower in PiMM patients (p<0.01). PiSZ patients are less susceptible to cigarette smoke than PiZZ. The pattern of emphysema may be similar at diagnosis to usual COPD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Thorax 07/2015; DOI:10.1136/thoraxjnl-2015-206906 · 8.56 Impact Factor
  • CE Green · D. Parr · RA Stockley · AM Turner
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    ABSTRACT: introduction and objectives Alpha-1-Antitrypsin Deficiency (A1ATD) is a genetically determined anti-proteinase deficiency which predisposes to emphysema.1 Factors predicting mortality in untreated A1ATD patients include poor FEV1, gas transfer and low lung density.1 Indeed the latter has been shown to be the most sensitive measure of progression and hence has become the primary outcome in recent studies of augmentation therapy.2 We hypothesised that patients with the most rapid decline in lung density would be those most at risk of death and most in need of transplantation as the only viable rescue option. Methods Augmentation naïve patients with 2 quantitative CT scans were selected from the UK A1ATD registry. The annual decline in lung density was determined using the difference between the 2 scans and patients were divided into those with no decline, a slow decline (0–2 g/l/year) or a rapid decline (> 2). Subsequent death or lung transplant was noted. A univariate analysis was undertaken dividing the population into 2 groups: Alive without transplant and dead. Median baseline density was significantly higher in the living than the dead group (55.40 g/l and 39.80 g/l respectively; p = 0.002) and thus was included in a multivariate analysis, seeking association with subsequent death in a Cox regression analysis. Results 77 patients were identified with sufficient data for analysis. 27 had died and 1 was transplanted and excluded from further analysis. Slow decline in densitometry showed a trend to lower survival compared to no decline (p = 0.065) but rapid decline was significantly associated with death (p = 0.026; Figure). Conclusions Decline in lung density may be a suitable surrogate measure for survival in AATD, and as augmentation therapy slows the decline in lung density2 could identify a group more likely to benefit from augmentation in the shorter term. References
    Thorax 12/2014; 69(Suppl 2):A12-A12. DOI:10.1136/thoraxjnl-2014-206260.24 · 8.56 Impact Factor
  • GM Walton · T. Purvis · C. Chadwick · RA Stockley · E. Sapey
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    ABSTRACT: Rationale All COPD phenotypes have airway neutrophilia but,despite this, bacteria associated infections are common, relate to decline and a significant proportion of patients have persistent airway colonisation. This is suggestive of innate immune dysfunction. In vitro studies have shown reduced neutrophil migratory accuracy in COPD (Sapey, Stockley et al. 2011) however, the ability of the neutrophil to contain bacterial infection upon arrival at a site of infection is poorly understood. Literature regarding the phagocytic ability of neutrophils from patients with COPD is conflicting and inconclusive. It is unclear whether responses change depending on the bacterial species present. We hypothesised that neutrophil phagocytosis during COPD is impaired, predisposing patients to increased inflammation and reduced bacterial clearance. Methods Blood neutrophils were isolated from stable-state COPD patients and healthy age-matched controls (HC). Phagocytosis of both opsonised (with 10% pooled COPD serum) and unopsonised pHrodo™-conjugated Staphylococcus aureus bioparticles (SA, n = 20), or Escherichia coli bioparticles (EC, n = 10) and fluorescently labelled disease-relevant bacteria, Haemophilus influenzae (HI, n = 10) and Streptococcus pneumoniae (SP, n = 10) was assessed, at regular intervals over 60 min, using flow-cytometry. Results were confirmed using time-lapse video microscopy. Results Peak phagocytosis was achieved at 60 min for unopsonised bacteria and 30 min for opsonised bacteria. There were no differences in time to peak phagocytosis between bacterial species. Blood neutrophils from patients with COPD and HC displayed similar phagocytic ability, in both percentage of neutrophils with phagocytic activity and the amount of SA, EC, HI or SP ingested (as indicated by MFI) (COPD vs. HC, p > 0.05 for all). This was ubiquitous to both opsonin independent and opsonin-dependant phagocytosis, and was consistent across all time points measured. A typical comparison is shown in figure one, with unopsonised SA data. Conclusions Phagocytic ability of blood neutrophils from patients with COPD to ingest Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae and Haemophilus influenzae is not altered compared to age-matched healthy controls. This should be replicated in lung neutrophils to assess whether transmigration to the tissues affects function.
    Thorax 12/2014; 69(Suppl 2):A26-A27. DOI:10.1136/thoraxjnl-2014-206260.52 · 8.56 Impact Factor
  • S. Vayalapra · RG Edgar · D. Griffiths · RA Stockley · AM Turner
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    ABSTRACT: Introduction Alpha-1 antitrypsin deficiency (AATD) is a hereditary disorder affecting about 1 in 3000 people in the UK commonly associated with early-onset emphysema. There are two common deficiency alleles - PiS and PiZ. PiZZ patients have severe AATD, with levels of 10–15% normal. PiSZ patients have less severe deficiency (≈ 40% normal) and are generally thought to have a minimal risk. We hypothesised that if PiSZ patients were at lower risk of COPD than PiZZ, and their lung disease would be more characteristic of usual COPD than that of PiZZ patients. Method 104 PiSZ patients and 638 PiZZ patients from the UK AATD registry (ADAPT) were compared for their demographics, lung function, risk factors for COPD (e.g. smoking, occupation), co-morbidities associated with COPD, index status (i.e. if diagnosed due to lung disease or family screening) and CT densitometry (where available). Outcome in terms of lung function decline and mortality was also assessed. Univariate statistics were used to guide subsequent regression analyses. Results Emphysema was more likely in PiZZ than PiSZ patients (OR 11.0 (5.7–21.3); p < 0.001) in the regression analysis after accounting for age, pack years and lung index status. PiZZ patients also had significantly worse FEV1 and DLCO than PiSZ patients in similar regression models (both p < 0.01). Emphysema was more severe in both upper and lower zone (both p < 0.01), and proportionately greater in the lower zone (UZ/LZ VI = 1.5 v 1.2) in PiZZ patients. Mortality and DLCO decline were also greater in PiZZ patients. Conclusion PiSZ patients have a milder form of AATD associated with better lung function. The data suggests the pattern of emphysema is closer to usual COPD than classical AATD. Further analyses comparing PiSZ to PiMM are now ongoing.
    Thorax 12/2014; 69(Suppl 2):A100-A100. DOI:10.1136/thoraxjnl-2014-206260.199 · 8.56 Impact Factor
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory condition with a complex pathophysiology. In COPD, the immune response involves the adaptive immune system, although the antigenic stimulus driving this response is unknown. During the process of antibody synthesis an excess of free light chains (FLCs) are produced and secreted into the circulation. High polyclonal FLC concentrations have been found in several autoimmune and inflammatory conditions such as systemic lupus erythematosus and rheumatoid arthritis. Thus, FLCs are being investigated as a biomarker of immune activation, disease activity, and severity in these conditions. Our aim was to establish whether serum FLCs could be a marker of phenotypic variation or predict poor outcome in patients with usual and alpha-1-antitrypsin deficiency (A1ATD)-related COPD.
    The Lancet 02/2014; 383:S28. DOI:10.1016/S0140-6736(14)60291-9 · 45.22 Impact Factor
  • Thorax 11/2013; 68(Suppl 3):A59-A60. DOI:10.1136/thoraxjnl-2013-204457.121 · 8.56 Impact Factor
  • J. A. Brebner · A. M. Turner · R. A. Stockley
    Thorax 11/2013; 68(Suppl 3):A34-A34. DOI:10.1136/thoraxjnl-2013-204457.69 · 8.56 Impact Factor
  • H Stone · A Pye · R.A. Stockley
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    ABSTRACT: In addition to emphysema alpha-1-antitrypsin deficiency (AATD) has been shown to be associated with several inflammatory conditions, including bronchiectasis, vasculitis, (in particular Wegener's granulomatosis), and panniculitis, suggesting neutrophil proteinases also play a role in their pathophysiology. However, it remains unknown whether other inflammatory diseases are also more prevalent in AATD than the general population. The current study describes the prevalence of other co-morbidities in AATD with particular emphasis on inflammatory bowel disease. The case notes of 651 PiZZ or PiZnull patients attending the UK national centre for AATD between 1996 and 2011 were reviewed. The prevalence of inflammatory bowel disease (1.5%) was higher than that predicted in the UK (0.4%). Ten patients had a confirmed diagnosis of ulcerative colitis, and 1 had Crohn's disease. In 2 cases there was a family history of inflammatory bowel disease and all but 1 patient were ex or never smokers. There was also a higher prevalence of hypothyroidism in this patient group than expected for the UK population - 26 cases (7.2% of females and 1.3% of males). The current study of the UK cohort of patients with AATD confirmed a higher prevalence of ulcerative colitis than would be expected in the general population, providing further evidence of a potential link between these 2 conditions. In addition, the data suggested a potential link between hypothyroidism and AATD.
    Respiratory medicine 10/2013; 108(2). DOI:10.1016/j.rmed.2013.10.006 · 2.92 Impact Factor
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    ABSTRACT: Abstract Knowledge about the pathogenesis and pathophysiology of chronic obstructive pulmonary disease (COPD) has advanced dramatically over the last 30 years. Unfortunately, this has had little impact in terms of new treatments. Over the same time frame, only one new class of medication for COPD has been introduced. Even worse, the rate at which new treatments are being developed is slowing. The development of new tools for the assessment of new treatments has not kept pace with understanding of the disease. In part, this is because drug development tools require a regulatory review, and no interested party has been in a position to undertake such a process. In order to facilitate the development of novel tools to assess new treatments, the Food and Drug Administration, in collaboration with the COPD Foundation, the National Heart Lung and Blood Institute and scientists from the pharmaceutical industry and academia conducted a workshop to survey the available information that could contribute to new tools. Based on this, a collaborative project, the COPD Biomarkers Qualification Consortium, was initiated. The Consortium in now actively preparing integrated data sets from existing resources that can address the problem of drug development tools for COPD.
    COPD Journal of Chronic Obstructive Pulmonary Disease 06/2013; 10(3):367-377. DOI:10.3109/15412555.2012.752807 · 2.62 Impact Factor
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    ABSTRACT: Neutrophil elastase (NE) activity is increased in bronchiectasis and may play a role in this condition. We wished to determine the effect of AZD9668, a selective oral inhibitor of NE. Efficacy and safety of AZD9668 60 mg twice daily over 4 weeks were evaluated in a randomised, double-blind, placebo-controlled, parallel-group, Phase II, signal-searching study in patients with bronchiectasis. Outcome measures included: waking and post-waking sputum neutrophil counts; lung function tests; 24-h sputum weight; BronkoTest(®) diary card data; St George's Respiratory Questionnaire for COPD patients (SGRQ-C); sputum NE activity; inflammatory biomarker levels; desmosine levels; adverse events, safety haematology and biochemistry. AZD9668 levels in plasma and sputum were measured to confirm exposure. Thirty-eight patients were randomised: 16 to placebo and 22 to AZD9668. There was no change in sputum neutrophils with AZD9668. Forced expiratory volume in 1 s improved by 100 mL in the AZD9668 group compared with placebo (p = 0.006). Significant changes (defined a priori as p < 0.1) in favour of AZD9668 were also seen in slow vital capacity, plasma interleukin-8, and post-waking sputum interleukin-6 and Regulated on Activation, Normal T-cell Expressed and Secreted levels. Non-significant changes in favour of AZD9668 were seen in other lung function tests, sputum weight and the SGRQ-C. AZD9668 was well tolerated. In this small signal-searching study, 4 weeks' treatment with AZD9668 improved lung function in patients with bronchiectasis and there were trends for reductions in sputum inflammatory biomarkers. Larger studies of longer duration would be needed to confirm the potential benefits of this agent in bronchiectasis. Registration: NCT00769119.
    Respiratory medicine 02/2013; 107(4). DOI:10.1016/j.rmed.2012.12.009 · 2.92 Impact Factor
  • R A Stockley
    COPD Journal of Chronic Obstructive Pulmonary Disease 01/2013; DOI:10.3109/15412555.2013.758442 · 2.62 Impact Factor
  • M. J. Ungurs · N. J. Sinden · R. A. Stockley
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    ABSTRACT: Background Progranulin (PGRN) is an anti-inflammatory protein, which is converted into pro-inflammatory granulin peptides (GRNs) by neutrophil elastase (NE) and proteinase-3 (PR3) (1). Neutrophilic inflammation is implicated in the pathophysiology of COPD, therefore the influence of PGRN on mechanisms of neutrophilic inflammation may be of great relevance to understanding and treating inflammation in the disease. Methods Sputum and serum samples were obtained from COPD patients with chronic bronchitis at exacerbation and in the subsequent clinically stable state. Sputum samples were graded by purulence and cultured for quantitative microbiology. PGRN was measured in sputum sol phase together with leukotriene B4 (LTB4), interleukin 8 (IL-8), myeloperoxidase (MPO), tumour necrosis factor α (TNFα), NE and PR3. PGRN and C-reactive protein (CRP) were measured in the serum. Results PGRN was lower in purulent sputum (median=38.91 ng/ml (IQR=1.55–89.71 ng/ml)) than mucoid (median=79.78 ng/ml (IQR=51.57–111.24 ng/ml)) (p=0.024, n=69). In purulent sputum PGRN correlated negatively with bacterial load and markers of inflammation (Table 1). Serum PGRN did not correlate with CRP, but was higher in stable COPD patients (median=65.71 ng/ml (IQR=0–86.46 ng/ml)) than healthy controls (median=38.55 ng/ml (IQR=36.11–44.82 ng/ml)) (p=<0.001, n=20), and increased further during purulent exacerbations (median=75.43 ng/ml (IQR=64.83–85.28 ng/ml)) (p=0.010, n=25). Conclusion The concentration of PGRN in the lung is associated with the increased inflammation seen with bacterial infection and exacerbation as assessed by markers of inflammation. The conversion of PGRN to GRNs may provide a mechanism by which neutrophil proteases regulate inflammation in COPD. Elevated circulating PGRN may reflect systemic inflammation associated with COPD.
    Thorax 12/2012; 67(Suppl 2):A174-A174. DOI:10.1136/thoraxjnl-2012-202678.311 · 8.56 Impact Factor
  • D. Whitters · T. J. Wells · I. R. Henderson · R. A. Stockley
    Thorax 11/2012; 67(Suppl 2):A51-A51. DOI:10.1136/thoraxjnl-2012-202678.110 · 8.56 Impact Factor
  • N. J. Sinden · E. Sapey · G. M. Walton · R. A. Stockley
    Thorax 11/2012; 67:A41-A42. DOI:10.1136/thoraxjnl-2012-202678.091 · 8.56 Impact Factor
  • H. M. Stone · R. Edgar · R. A. Stockley
    Thorax 11/2012; 67(Suppl 2):A99-A99. DOI:10.1136/thoraxjnl-2012-202678.323 · 8.56 Impact Factor
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • H. Stone · A. Pye · R. A. Stockley
    Thorax 12/2011; 66(Suppl 4):A86-A86. DOI:10.1136/thoraxjnl-2011-201054c.45 · 8.56 Impact Factor
  • P. R. Newby · C. Schmutz · C. R. Buckley · R. A. Stockley · A. M. Wood
    Thorax 12/2011; 66(Suppl 4):A38-A38. DOI:10.1136/thoraxjnl-2011-201054b.78 · 8.56 Impact Factor
  • N. J. Sinden · M. Ungurs · R. Edgar · P. Bharadwa · R. A. Stockley
    Thorax 12/2011; 66(Suppl 4):A37-A37. DOI:10.1136/thoraxjnl-2011-201054b.76 · 8.56 Impact Factor

Publication Stats

7k Citations
1,712.22 Total Impact Points

Institutions

  • 1978–2014
    • University of Birmingham
      • • School of Clinical and Experimental Medicine
      • • School of Immunity and Infection
      Birmingham, England, United Kingdom
  • 2001–2013
    • The Queen Elizabeth Hospital
      Tarndarnya, South Australia, Australia
  • 1987–2013
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom
    • The Royal Orthopaedic Hospital NHS Foundation Trust
      Birmingham, England, United Kingdom
  • 1990–2012
    • University Hospitals Birmingham NHS Foundation Trust
      • Department of Respiratory Medicine
      Birmingham, England, United Kingdom
    • Barnes Jewish Hospital
      San Luis, Missouri, United States
  • 2002
    • Policlinico San Matteo Pavia Fondazione IRCCS
      Ticinum, Lombardy, Italy
  • 1994
    • University of Queensland
      • Department of Medicine
      Brisbane, Queensland, Australia
    • University of Cambridge
      • Department of Haematology
      Cambridge, England, United Kingdom
  • 1985
    • Leiden University
      Leyden, South Holland, Netherlands