[Show abstract][Hide abstract] ABSTRACT: Although specific antibody induced by pathogens or vaccines is a key component of protection against infectious threats, some viruses, such as dengue, induce antibody that enhances the development of infection. In contrast, antibody-dependent enhancement of bacterial infection is largely unrecognized. Here, we demonstrate that in a significant portion of patients with bronchiectasis and Pseudomonas aeruginosa lung infection, antibody can protect the bacterium from complement-mediated killing. Strains that resist antibody-induced, complement-mediated killing produce lipopolysaccharide containing O-antigen. The inhibition of antibody-mediated killing is caused by excess production of O-antigen-specific IgG2 antibodies. Depletion of IgG2 to O-antigen restores the ability of sera to kill strains with long-chain O-antigen. Patients with impaired serum-mediated killing of P. aeruginosa by IgG2 have poorer respiratory function than infected patients who do not produce inhibitory antibody. We suggest that excessive binding of IgG2 to O-antigen shields the bacterium from other antibodies that can induce complement-mediated killing of bacteria. As there is significant sharing of O-antigen structure between different Gram-negative bacteria, this IgG2-mediated impairment of killing may operate in other Gram-negative infections. These findings have marked implications for our understanding of protection generated by natural infection and for the design of vaccines, which should avoid inducing such blocking antibodies.
[Show abstract][Hide abstract] ABSTRACT: Rationale It is not known how the 2011 Global Initiative on Chronic Obstructive Lung Disease (GOLD) strategy predicts clinical course of Alpha One Antitrypsin Deficiency (AATD). Objectives To determine how the new strategy relates to outcomes i.e. mortality, lung function decline and exacerbations in patients with AATD. Methods All PiZZ patients on the AATD registry with a physiological diagnosis of Chronic Obstructive Pulmonary Disease (COPD) were grouped into four GOLD categories (A, B, C, and D) on the basis of their combined risk. We then compared mortality and lung function decline in these categories and also assessed the predictive ability of exacerbation history in the patients. Measurements and Main Results Mortality [A 6 (5.8%), B 7 (5.93%), C 11 (9.32%), D 94 (79.66%)] was greatest in high symptom, high risk Group D (2p = 0.0001) which also showed a faster decline in Kco [A-0.021 (0.03), B -0.022 (0.03), C -0.032 (0.03), D -0.031 (0.03)] (2p= 0.012). The fastest mean decline in FEV1 [A -66.59 (61.39), B -53.00 (47.09), C -56.96 (48.87), D -41.25 (62.09)] was observed in Group A and least in Group D (2p = 0.002). Multivariate analysis showed that GOLD category was significant for all outcomes (2p < 0.05). Conclusions The new strategy performs well in identifying patients with increased risk of poorer outcomes in AATD. This has therapeutic implications enabling more aggressive therapy to be directed to those in the highest risk group. Further studies to identify sub group of patients most likely to benefit from augmentation therapy are indicated.
[Show abstract][Hide abstract] ABSTRACT: Alpha1-antitrypsin (AAT) deficiency was first described in 1963 together with its associations with severe early-onset basal panacinar emphysema. The genetic defects leading to deficiency have been elucidated and the pathophysiologic processes, clinical variation in phenotype, and the role of genetic modifiers have been recognized. Strategies to increase plasma (and hence tissue) concentrations of AAT have been developed. The only recognized specific therapeutic strategy is regular infusions of the purified plasma protein, and evidence confirms its efficacy in protecting the lung (at least partially). Early detection and modification of lifestyle remains crucial to the management of AAT deficiency.
Clinics in chest medicine 03/2014; 35(1):39-50. · 2.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract It is increasingly recognised that new measures of disease 'activity' for COPD are required, however the relationship between markers of disease 'activity', 'severity' and 'impact' though closely linked, is poorly understood. Additionally, while change in markers of disease 'severity' (e.g. change in FEV1) may be considered a marker of disease 'activity', these quantify a single aspect of disease 'activity' in COPD rather than measuring the overall disease process and this has stimulated the search for new biomarkers of COPD that reflect the 'activity' of the disease process. The ideal biomarker of disease 'activity' would be stable with respect to time since measurement at any time point would then relate to subsequent disease progression. This would allow the influence of a therapeutic intervention to be assessed early, facilitating both phase 2 and 3 clinical trials. Although a number of potential biomarkers of COPD disease 'activity' have been studied, to date none have been shown to conclusively relate to disease progression and the stability of underlying disease 'activity' therefore requires further consideration. Interestingly, while the variability of disease 'activity' of COPD is rarely mentioned in the current literature, and there is uncertainty whether 'activity' is constant or highly variable, there are clues from available data as discussed in the current article. Finally we consider how markers of disease 'activity', 'severity' and 'impact' may relate, which is of utmost importance in the ongoing search for new biomarkers in COPD and a greater understanding of the pathogenesis of the disease process.
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT (N=212) Phenotypic differences in physiological, radiological and clinical characteristics are increasingly recognised in COPD. The factors associated with alpha-1-antitrypsin deficiency (A1AD) physiological phenotypes and how they progress with time have yet to be explained.530 PiZZ A1AD patients were studied; 255 of whom had ≥3 years data for longitudinal analysis. Patients were categorized into 4 groups using lower limits of normal for Kco and post-bronchodilator FEV1/FVC ratio. Group comparisons were undertaken for demographic, clinical, physiological, health status, survival and CT data.Groups with normal lung function or isolated gas transfer defect had the lowest smoking history, least emphysema and best health status. The group with airflow obstruction alone (AO) had a greater smoking history, more emphysema and worse health status compared to the normal group. The group with combined airflow obstruction and gas transfer defect were the worst. The group with AO alone had a faster subsequent decline in Kco than the normal group (p=0.002) and the group with both AO and reduced gas transfer (p<0.001) and were more likely to change group with time (62% moving to group B). Lower baseline Kco and male sex predicted 89% of the movement to the group with both physiological abnormalities.There are distinct physiological phenotypes in A1AD with differing demographic features that relate to progression.
[Show abstract][Hide abstract] ABSTRACT: The field of biomarker research has almost reached unmanageable proportions in chronic obstructive pulmonary disease (COPD). The developments of new technology platforms have generated a huge information data base, both cross sectionally and increasingly, longitudinally. The knowledge emerging provides an enormous potential for understanding the disease pathophysiology, for developing markers specific for long-term outcomes, and for developing new therapeutic strategies. However, the excitement must be tempered with an understanding of the limitations of the data collection techniques, and of the variations in disease state, activity, impact, and progression. Nevertheless, the most crucial aspect in interpreting the current literature is the recognition of the relatively superficial characterization of what is a complex group of pathological processes with a common end point of airflow limitation. The current review explores some of these issues together with those areas where real progress appears to have been made, and provides caution on interpretation.
[Show abstract][Hide abstract] ABSTRACT: Background
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.
We measured FLC concentrations in 294 COPD patients with A1ATD-related and 85 patients with usual COPD using the Freelite serum FLC assay (The Binding Site Ltd, Birmingham, UK). We then compared combined (κ and λ) FLC (cFLC) concentrations in different subgroups defined by the presence of chronic bronchitis, colonisation of the lower respiratory tract, and subsequent mortality. In addition, we measured the estimated glomerular filtration rate (eGFR) of patients included in the study.
Our preliminary data showed that in A1ATD-related COPD and usual COPD, cFLC concentrations were significantly higher in patients with chronic bronchitis than in those without bronchitis (p=0·008 vs p=0·047). Patients with A1ATD-related COPD who were chronically colonised with pathogenic organisms in their stable state also had significantly higher cFLC concentrations than did those who were not colonised (p=0·036). A multiple regression analysis showed that eGFR and the presence of chronic bronchitis significantly predicted cFLC concentrations in patients with A1ATD: renal function was the strongest predictor (β=−0·326, p<0·0001) followed by the presence of chronic bronchitis (β=0·147, p=0·01). A similar trend was seen in the usual COPD group although this did not meet statistical significance (eGFR β=−0·220, p=0·055; chronic bronchitis β=0·224, p=0·061). The 33 A1ATD patients who subsequently died also had significantly higher cFLC concentrations (p=0·005) than did those still alive.
The higher cFLC concentrations in patients with A1ATD-related COPD who have chronic bronchitis and colonised lower respiratory tracts could mean that there is a greater adaptive immune response in these individuals. The drive behind this response might come directly from microorganisms or through self-perpetuating autoimmune events. Within the specialty of COPD clinical management, there is a move towards a more individualised approach to treating different clinical phenotypes. Measurement of serum FLCs might have a potential role as a biomarker to help stratify patients. The higher cFLC concentrations in patients with renal impairment is unsurprising in view of their renal clearance, but raised polyclonal FLCs have also been shown to be a predictor of mortality in the general population. Our mortality results suggest that FLCs could have a role in risk stratification for patients with COPD, but further investigation is needed.
[Show abstract][Hide abstract] ABSTRACT: The recognition of α-1-antitrypsin deficiency, its function, and its role in predisposition to the development of severe emphysema was a watershed in our understanding of the pathophysiology of the condition. This led to the concept and development of intravenous replacement therapy used worldwide to protect against lung damage induced by neutrophil elastase. Nevertheless, much remained unknown about the deficiency and its impact, although in recent years the genetic and clinical variations in manifestation have provided new insights into assessing impact, efficacy of therapy, and development of new therapeutic strategies, including gene therapy, and outcome measures, such as biomarkers and computed tomography. The current article reviews this progress over the preceding 50 years.
Trends in Molecular Medicine 12/2013; · 9.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Immunesenescence is the functional deterioration of the immune system during natural aging. Despite increased susceptibility to bacterial infections in older adults age-associated changes to neutrophil responses are only partially understood and neutrophil migration has not been characterized in detail. Here we describe reduced chemotaxis but preserved chemokinesis towards a range of inflammatory stimuli in migrating neutrophils isolated from healthy older subjects. Cross-sectional data indicate that migratory behaviour changes in the sixth decade of life. Crucially, aberrant migration may increase "by-stander" tissue damage and heighten inflammation due to excess proteinase release during inaccurate chemotaxis, as well as reducing pathogen clearance. We show evidence of increased neutrophil proteinase activity in older adults, namely raised levels of neutrophil proteinase substrate-derived peptides and evidence of primary granule release, associated with increased systemic inflammation. Inaccurate migration was causally associated with increased constitutive Phosphoinositide 3-kinase (PI3K) signalling; untreated neutrophils from old donors demonstrated significant PI3K activation compared with cells from young donors. PI3K blocking strategies, specifically inhibition of PI3K γ or δ restored neutrophil migratory accuracy while SHIP1 inhibition worsened migratory flaws. Targeting PI3K signalling may therefore offer a new strategy in improving neutrophil functions during infections and reduce inappropriate inflammation in older patients.
[Show abstract][Hide abstract] ABSTRACT: Progranulin (PGRN) is an anti-inflammatory protein, yet its digestion by neutrophil-derived proteinases generates products that can stimulate epithelial cell lines to secrete the neutrophil chemoattractant IL-8. Since dysregulated neutrophilic inflammation is implicated in the pathophysiology of COPD the possible influence of PGRN and digestion products may be of relevance to understanding and treating inflammation in the disease. PGRN was measured in sputum sol-phase samples from patients with a clinical diagnosis of COPD and chronic sputum production in a clinically stable state, PGRN correlated negatively with bacterial load (CFU/ml) (r=-0.446, p=0.003, n=43) and markers of neutrophilic inflammation including NE (nM) (r=-0.562, p=0.008, n=21) and PR3 (nM) (r=-0.515, p=0.017, n=21). Products of PGRN digestion were detected in sputum sol-phase, and PGRN conversion activity in sputum sol-phase was inhibited with the serine proteinase inhibitor α1-antitrypsin. Digested PGRN at concentrations likely to be present in the airways did not stimulate IL-8 secretion from normal human bronchial epithelial (NHBE) cells. Infection of NHBE cells with live Haemophilus influenzae significantly increased PGRN secretion compared to untreated cells (p=<0.001). The concentration of PGRN relates negatively to the amplified airway inflammation associated with bacterial colonisation in clinically stable COPD. This relationship is driven by the proteolytic action of the neutrophil derived proteinases NE and PR3; the products released by this action are unlikely to stimulate significant IL-8 secretion from epithelial cells in the airways.
[Show abstract][Hide abstract] 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; · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intravenous augmentation therapy is the only specific treatment available for emphysema associated with alpha-1 antitrypsin deficiency. Despite large observational studies and limited interventional studies there remains controversy about the efficacy of this treatment due to the impracticality of conducting adequately powered studies to evaluate the rate of decline in lung function, due to the low prevalence and the slow progression of the disease. However, measurement of lung density by computed tomography is a more specific and sensitive marker of the evolution of emphysema and two small placebo-controlled clinical trials have provided evidence supporting a reduction in the rate of decline in lung density with augmentation therapy.The problem: Where augmentation therapy has become available there has been little consideration of a structured approach to therapy which is often introduced on the basis of functional impairment at diagnosis. Data from registries have shown a great variability in the evolution of lung disease according to patient acquisition and the presence of recognised risk factors. Avoidance of risk factors may, in many cases, stabilise the disease. Since augmentation therapy itself will at best preserve the presenting level of lung damage yet require intravenous administration for life with associated costs, identification of patients at risk of continued rapid or long term progression is essential to select those for whom this treatment can be most appropriate and hence generally more cost-effective. This represents a major reconsideration of the current practice in order to develop a consistent approach to management world wide.Purpose of this review: The current review assesses the evidence for efficacy of augmentation therapy and considers how the combination of age, physiological impairment, exacerbation history and rate of decline in spirometry and other measures of emphysema may be used to improve therapeutic decision making, until a reliable predictive biomarker of the evolution of lung impairment can be identified. In addition, individual pharmacokinetic studies may permit the selection of the best regimen of administration for those who need it.
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT BACKGROUND The new GOLD strategy recommends use of CAT or modified MRC scale to assess symptoms in COPD against "risk" as assessed by spirometry or exacerbation frequency. We aimed to determine the concordance between CAT and modified MRC scale in assessing risk in patients with AATD and the CAT threshold for risk assessment at which similar proportion of patients are assigned into the risk categories. METHODS Distribution of 309 patients (PiZZ) in four GOLD categories (A, B, C, and D) was compared. Using CAT for symptoms, we compared patient distribution using scores between 10 and 15 to ascertain the CAT threshold at which the distribution of patients in each group is proportional. RESULTS Using CAT 10 and spirometry for risk assessment, 6.1% patients were in group A (low symptoms/low risk); 39.2% in B (high symptoms /low risk); 2.3% in C (low symptoms/high risk) and 52.4% in D (high symptoms/high risk). Using mMRC and spirometry for risk produced a significantly different distribution to that using CAT (p<0.0001).Using CAT 13 as symptom threshold and spirometry for risk, resulted in a more proportional distribution of patients which was similar using CAT and exacerbation history (p>0.0001) and mMRC and spirometry and/or exacerbation history for risk (p>0.0001). CONCLUSIONS In patients with AATD, using either the MRC 0-1 or CAT 10 scores to determine symptoms, results in a significant difference in patient distribution. However CAT 13 as the threshold for assessing symptoms results in a similar proportion of patients being categorised into the risk categories.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: α-1-antitrypsin deficiency (A1ATD) is an under-recognized hereditary disorder associated with the premature onset of chronic obstructive pulmonary disease. There is considerable heterogeneity in the phenotypic expression of lung disease in A1ATD and the pathophysiology is complex, involving the interaction of multiple pathways. Other genetic factors that may contribute to emphysema risk in A1AT-deficient individuals are beginning to be identified. Methods of monitoring disease progression have evolved, including the use of computed tomography densitometry and biomarkers of disease activity. Progress in the development of novel treatment strategies continues, including the hope for a potential cure through the use of gene therapies. In this article, the authors review the recent advances in this field and outline potential future directions of research in A1ATD.
Expert Review of Respiratory Medicine 06/2013; 7(3):213-30.
[Show abstract][Hide abstract] ABSTRACT: AATD is a European genetic condition that has disseminated along human migration routes. The discovery, function, phenotyping methodologies and biochemical mechanisms have been led by several European countries. The variable availability of augmentation therapy has permitted a better understanding of the natural history and the ability to deliver controlled clinical trials. The establishment of a worldwide registry remains central to the future of understanding and managing AATD.