Janet G. Shaw

Mannose-binding lectin gene polymorphism predicts hospital admissions for COPD infections

Infection frequently causes exacerbations of chronic obstructive pulmonary disease (COPD). Mannose-binding lectin (MBL) is a pattern-recognition receptor that assists in clearing microorganisms. Polymorphisms in the MBL2 gene reduce serum MBL levels and are associated with risk of infection. We studied whether the MBL2 codon 54 B allele affected serum MBL levels, admissions for infective exacerbation in COPD and disease susceptibility. Polymorphism frequency was determined by PCR-RFLP in 200 COPD patients and 104 smokers with normal lung function. Serum MBL was measured as mannan-binding activity in a subgroup of 82 stable COPD patients. Frequency of COPD admissions for infective exacerbation was ascertained for a 2-year period. The MBL2 codon 54 B allele reduced serum MBL in COPD patients. In keeping, patients carrying the low MBL-producing B allele had increased risk of admission for infective exacerbation (OR 4.9, Pcorrected=0.011). No association of MBL2 genotype with susceptibility to COPD was detected. In COPD, serum MBL is regulated by polymorphism at codon 54 in its encoding gene. Low MBL-producing genotypes were associated with more frequent admissions to hospital with respiratory infection, suggesting that the MBL2 gene is disease-modifying in COPD. MBL2 genotype should be explored prospectively as a prognostic marker for infection risk in COPD.

Biomarkers of progression of chronic obstructive pulmonary disease (COPD)

Disease progression of chronic obstructive pulmonary disease (COPD) is variable, with some patients having a relatively stable course, while others suffer relentless progression leading to severe breathlessness, frequent acute exacerbations of COPD (AECOPD), respiratory failure and death. Radiological markers such as CT emphysema index, bronchiectasis and coronary artery calcification (CAC) have been linked with increased mortality in COPD patients. Molecular changes in lung tissue reflect alterations in lung pathology that occur with disease progression; however, lung tissue is not routinely accessible. Cell counts (including neutrophils) and mediators in induced sputum have been associated with lung function and risk of exacerbations. Examples of peripheral blood biological markers (biomarkers) include those associated with lung function (reduced CC-16), emphysema severity (increased adiponectin, reduced sRAGE), exacerbations and mortality [increased CRP, fibrinogen, leukocyte count, IL-6, IL-8, and tumor necrosis factor α (TNF-α)] including increased YKL-40 with mortality. Emerging approaches to discovering markers of gene-environment interaction include exhaled breath analysis [volatile organic compounds (VOCs), exhaled breath condensate], cellular and systemic responses to exposure to air pollution, alterations in the lung microbiome, and biomarkers of lung ageing such as telomere length shortening and reduced levels of sirtuins. Overcoming methodological challenges in sampling and quality control will enable more robust yet easily accessible biomarkers to be developed and qualified, in order to optimise personalised medicine in patients with COPD.

Acute exacerbation of COPD

The literature of acute exacerbation of chronic obstructive pulmonary disease (COPD) is fast expanding. This review focuses on several aspects of acute exacerbation of COPD (AECOPD) including epidemiology, diagnosis and management. COPD poses a major health and economic burden in the Asia‐Pacific region, as it does worldwide. Triggering factors of AECOPD include infectious (bacteria and viruses) and environmental (air pollution and meteorological effect) factors. Disruption in the dynamic balance between the ‘pathogens’ (viral and bacterial) and the normal bacterial communities that constitute the lung microbiome likely contributes to the risk of exacerbations. The diagnostic approach to AECOPD varies based on the clinical setting and severity of the exacerbation. After history and examination, a number of investigations may be useful, including oximetry, sputum culture, chest X‐ray and blood tests for inflammatory markers. Arterial blood gases should be considered in severe exacerbations, to characterize respiratory failure. Depending on the severity, the acute management of AECOPD involves use of bronchodilators, steroids, antibiotics, oxygen and noninvasive ventilation. Hospitalization may be required, for severe exacerbations. Nonpharmacological interventions including disease‐specific self‐management, pulmonary rehabilitation, early medical follow‐up, home visits by respiratory health workers, integrated programmes and telehealth‐assisted hospital at home have been studied during hospitalization and shortly after discharge in patients who have had a recent AECOPD. Pharmacological approaches to reducing risk of future exacerbations include long‐acting bronchodilators, inhaled steroids, mucolytics, vaccinations and long‐term macrolides. Further studies are needed to assess the cost‐effectiveness of these interventions in preventing COPD exacerbations.

Mucociliary clearance in patients with chronic asthma: effects of beta agonists.

Objective:  Chronic asthma is characterized by airway inflammation, mucus hypersecretion and impaired mucociliary clearance (MCC). We investigated baseline MCC and the acute effect of terbutaline in chronic asthmatics with sputum production while on long‐term treatment with salmeterol in combination with inhaled corticosteroids (ICS).

Peripheral compartment innate immune response to Haemophilus influenzae and Streptococcus pneumoniae in chronic obstructive pulmonary disease patients

Alterations in innate immunity that predispose to chronic obstructive pulmonary disease (COPD) exacerbations are poorly understood. We examined innate immunity gene expression in peripheral blood polymorphonuclear leukocytes (PMN) and monocytes stimulated by Haemophilus influenzae and Streptococcus pneumoniae. Thirty COPD patients (15 rapid and 15 non-rapid lung function decliners) and 15 smokers without COPD were studied. Protein expression of IL-8, IL-6, TNF-α and IFN-γ (especially monocytes) increased with bacterial challenge. In monocytes stimulated with S. pneumoniae, TNF-α protein expression was higher in COPD (non-rapid decliners) than in smokers. In co-cultures of monocytes and PMN, mRNA expression of TGF-β1 and MYD88 was up-regulated, and CD14, TLR2 and IFN-γ down-regulated with H. influenzae challenge. TNF-α mRNA expression was increased with H. influenzae challenge in COPD. Cytokine responses were similar between rapid and non-rapid decliners. TNF-α expression was up-regulated in non-rapid decliners in response to H. influenzae (monocytes) and S. pneumoniae (co-culture of monocytes and PMN). Exposure to bacterial pathogens causes characteristic innate immune responses in peripheral blood monocytes and PMN in COPD. Bacterial exposure significantly alters the expression of TNF-α in COPD patients, although not consistently. There did not appear to be major differences in innate immune responses between rapid and non-rapid decliners.

Personalizing and targeting therapy for COPD: the role of molecular and clinical biomarkers.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by persistent airflow limitation. It is the third leading cause of death worldwide, and there are currently no curative strategies for this disease. Many factors contribute to COPD susceptibility, progression and exacerbations. These include cigarette smoking, environmental and occupational pollutants, respiratory infections and comorbidities. As the clinical phenotypes of COPD are so variable, it has been difficult to devise an individualized treatment plan for patients with this complex chronic disease. This review will highlight how potential clinical, inflammatory, genomic and epigenomic biomarkers for COPD could be used to personalize treatment, leading to improved disease management and prevention for our patients.

Genetic influences on right ventricular systolic pressure (RVSP) in chronic obstructive pulmonary disease (COPD)

BackgroundPulmonary hypertension (PH) is a complication of chronic obstructive pulmonary disease (COPD). This study examined genetic variations in mediators of vascular remodelling and their association with PH in patients with COPD. In patients with COPD, we genotyped 7 SNPs in 6 candidate PH genes (NOS3, ACE, EDN1, PTGIS, SLC6A4, VEGFA). We tested for association with right ventricular systolic pressure (RVSP), spirometry and gas transfer, and hypoxemia.MethodsIn patients with COPD, we genotyped 7 SNPs in 6 candidate PH genes (NOS3, ACE, EDN1, PTGIS, SLC6A4, VEGFA). We tested for association with right ventricular systolic pressure (RVSP), spirometry and gas transfer, and hypoxemia.Results580 COPD patients were recruited, 341 patients had a transthoracic echocardiogram, with RVSP measurable in 278 patients (mean age 69 years, mean FEV1 50% predicted, mean RVSP 44 mmHg, median history of 50 pack-years). Of the 7 tested SNPs, the NOS3-VNTR polymorphism was significantly associated with RVSP in a dose-dependent fashion for the risk allele: mean RVSP for a/a and a/b genotypes were 52.0 and 46.6 mmHg respectively, compared to 43.2 mmHg for b/b genotypes (P = 0.032). No associations were found between RVSP and other polymorphisms. ACE II or ID genotypes were associated with a lower FEV1% predicted than the ACE DD genotype (P = 0.028). The NOS3-298 TT genotype was associated with lower KCO % predicted than the NOS3-298 GG or GT genotype (P = 0.031).ConclusionsThe NOS3-VNTR polymorphism was associated with RVSP in patients with COPD, supporting its involvement in the pathogenesis of PH in COPD. ACE and NOS3 genotypes were associated with COPD disease severity, but not with the presence of PH. Further study of these genes could lead to the development of prognostic and screening tools for PH in COPD.

Detection of Microbial Pathogens Using a Multiple Target Quantitative Polymerase Chain Reaction (Qpcr) Array in Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a progressive condition comprising a constellation of disorders from chronic bronchitis, airflow obstruction through to emphysema. The global burden of COPD is estimated at more than 6% of the population. The standard of care is based on a combination of smoking cessation, immunization, pharmacological treatments and pulmonary rehabilitation. However, the more advanced stages of COPD are challenging to manage. In this situation, our current standards of care do not adequately control patient symptoms nor halt the progressive decline. For the emphysema phenotype, lung volume reduction surgery has shown a beneficial effect in selected patients but is counterbalanced by the morbidity experienced by some patients. Bronchoscopic volume reduction technologies have been developed to improve the clinical situation of emphysema patients. This presentation provides broad guidance regarding patient selection and the current position of the available techniques for patients with advanced emphysema. Conflict of interest Disclosure statement: Aboard activities for BTG, Broncus, Pulmonx, Olympus, Uptake

Use of inhaled corticosteroids in COPD: improving efficacy

ABSTRACT Chronic obstructive pulmonary disease (COPD) is a chronic, inflammatory lung disease characterized by airflow limitation that is not fully reversible. The pathological changes in COPD lead to alveolar destruction (emphysema) and chronic airway inflammation, resulting in airflow obstruction and recurrent exacerbations. Inhaled corticosteroids (ICS) are anti-inflammatory agents that are widely used, especially in combination with long-acting beta-agonists, in patients with COPD. Here, we will summarize the benefits and risks of ICS use for COPD, and discuss approaches to more personalized medicine when selecting COPD patients to commence (or withdraw) ICS use. The conclusion arising is that further validation of clinical and biological markers should be undertaken in COPD, in order to individualize ICS therapy to maximize efficacy for patients.

Screening lung Tumour tissue for whole genome sequencing

068-P12 LUNG ADENOCARCINOMA BIOMARKER SCREENING IN AN AUSTR`ALIAN POPULATION Ainge Allen H, Stone E, Plit Ml, Havryk A, Goldrick A, Field A, Mead S, Qiu M, Chou A, Morey A Department of Respiratory Medicine, St Vincent’s Hospital, Sydney, New South Wales/AUSTRALIA; Department of Anatomical Pathology, Sydpath, St Vincent’s Hospital, Sydney, New South Wales/AUSTRALIA Aims: The emergence of new targeted therapies and clinical trials in lung adenocarcinoma suggest that routine molecular biomarker testing is warranted to detected subtypes of adenocarcinoma which will benefit from new therapies. Australian data is still emerging. We aim to detect the incidence of treatment specific molecular subtypes of lung adenocarcinoma in the Australian population. Methods: This is a single centre prospective pilot study of patients with a histopathological diagnosis of adenocarcinoma who have been presented at a Lung Cancer multidisciplinary meeting. Formalin fixed paraffin embedded tissue of 22 tumour samples were submitted for targeted PCR-based EGFR and KRAS mutation analysis; and EGFR amplification, MET amplification and EML4-ALK rearrangement testing by in-situ hybridization. one sample had insufficient tissue for analysis. Results: So far 22 patients received a definite tissue diagnosis of lung adenocarcinoma, 8/22 with Stage III and 10/22 with Stage IV disease. 4/22 (19%) are positive for an EGFR mutation, with activating EGFR mutations in 3/22 (14%) and an EGFR mutation of uncertain clinical significance in one patient (5%). EGFR amplification was detected in 2/22 patients (9%), KRAS mutations were detected in 5/22 patients (23%) patients, of which none carried EGFR mutations. EML4-ALK translocation was seen in 2/22 patients (9%) and MET amplification in 1/22 (5%) patients. Conclusions: Preliminary results indicate that treatment specific molecular subtypes of lung adenocarcinoma occur more commonly in the Australia population than other Western populations. Though further investigation is required, routine molecular biomarker testing is warranted. Disclosure: This study was funded by an unrestricted grant from Roche.