Chr15q25 genetic variant (rs16969968) independently confers risk of lung cancer, COPD and smoking intensity in a prospective study of high-risk smokers.

IMPORTANCE: While cholinergic receptor nicotinic alpha 5 (CHRNA5) variants have been linked to lung cancer, chronic obstructive pulmonary disease (COPD) and smoking addiction in case-controls studies, their corelationship is not well understood and requires retesting in a cohort study. OBJECTIVE: To re-examine the association between the CHRNA5 variant (rs16969968 AA genotype) and the development of lung cancer, relative to its association with COPD and smoking. METHODS: In 9270 Non-Hispanic white subjects from the National Lung Screening Trial, a substudy of high-risk smokers were followed for an average of 6.4 years. We compared CHRNA5 genotype according to baseline smoking exposure, lung function and COPD status. We also compared the lung cancer incidence rate, and used multiple logistic regression and mediation analysis to examine the role of the AA genotype of the CHRNA5 variant in smoking exposure, COPD and lung cancer. RESULTS: As previously reported, we found the AA high-risk genotype was associated with lower lung function (p=0.005), greater smoking intensity (p<0.001), the presence of COPD (OR 1.28 (95% CI 1.10 to 1.49) p=0.0015) and the development of lung cancer (HR 1.41, (95% CI 1.03 to 1.93) p=0.03). In a mediation analyses, the AA genotype was independently associated with smoking intensity (OR 1.42 (95% CI 1.25 to 1.60, p<0.0001), COPD (OR 1.25, (95% CI 1.66 to 2.53), p=0.0015) and developing lung cancer (OR 1.37, (95% CI 1.03 to 1.82) p=0.03). CONCLUSION: In this large-prospective study, we found the CHRNA5 rs 16 969 968 AA genotype to be independently associated with smoking exposure, COPD and lung cancer (triple whammy effect).

Characteristics of sarcoidosis in Maori and Pacific Islanders.

BACKGROUND AND OBJECTIVE: Ethnicity is strongly associated with variable clinical presentation in sarcoidosis but the association between ethnicity and clinical characteristics has not previously been described in patients of Polynesian ancestry, Maori and Pacific Islander (PI). The objective of this study was to describe the clinical characteristics of sarcoidosis in Maori and PI patients and determine if those were different to European patients. METHODS: A retrospective review of the medical records of 406 patients (69 Maori/PI) attending a specialist interstitial lung disease (ILD) clinic. RESULTS: The population (207 females, mean age at presentation: 36) reflected the current New Zealand census data (2013) with only people of Indian ethnicity over-represented. Parenchymal lung involvement was uncommon in Maori and PI patients (21% Scadding stage 2, 2% stage 3), and no patient had extensive pulmonary fibrosis (stage 4). Computed tomography (CT) patterns of sarcoid parenchymal lung involvement were less commonly reported for Maori/PI. There were no differences in respect of baseline lung function or requirement for treatment. Ocular and skin involvement occurred more frequently in Maori and PI (P = 0.0045, P = 0.03), and erythema nodosum was more common in Caucasians (P = 0.0008). CONCLUSION: People of Polynesian ancestry appear to have less pulmonary and more extra-pulmonary manifestations of sarcoidosis. This adds to our knowledge that sarcoidosis heterogeneity is influenced by ethnicity.

The Gut-Liver-Lung Axis. Modulation of the Innate Immune Response and Its Possible Role in Chronic Obstructive Pulmonary Disease.

Evidence from epidemiological studies suggests that a diet high in fiber is associated with better lung function and reduced risk of chronic obstructive pulmonary disease (COPD). The mechanism for this benefit remains unknown, but, as fiber is not absorbed by the gut, this finding suggests that the gut may play an active role in pathogenic pathways underlying COPD. There is a growing awareness that aberrant activity of the innate immune system, characterized by increased neutrophil and macrophage activation, may contribute to the development or progression of COPD. Innate immunity is modulated in large part by the liver, where hepatic cells function in immune surveillance of the portal circulation, as well as providing a rich source of systemic inflammatory cytokines and immune mediators (notably, IL-6 and C-reactive protein). We believe that the beneficial effect of dietary fiber on lung function is through modulation of innate immunity and subsequent attenuation of the pulmonary response to inflammatory stimuli, most apparent in current or former smokers. We propose that the "gut-liver-lung axis" may play a modifying role in the pathogenesis of COPD. In this review, we summarize lines of evidence that include animal models, large prospective observational studies, and clinical trials, supporting the hypothesis that the gut-liver-lung axis plays an integral part in the pathogenic mechanisms underlying the pathogenesis of COPD.

Airflow Limitation and Histology Shift in the National Lung Screening Trial. The NLST-ACRIN Cohort Substudy.

RATIONALE: Annual computed tomography (CT) is now widely recommended for lung cancer screening in the United States, although concerns remain regarding the potential harms, including those from overdiagnosis. OBJECTIVES: To examine the effect of airflow limitation on overdiagnosis by comparing lung cancer incidence, histology, and stage shift in a subgroup of the National Lung Screening Trial (NLST). METHODS: In an NLST subgroup (n = 18,714), screening participants were randomized to annual computed tomography (CT, n = 9,357) or chest radiograph (n = 9,357) screening and monitored for a mean of 6.1 years. After baseline prebronchodilator spirometry, to identify the presence of airflow limitation, 18,475 subjects (99%) were assigned as having chronic obstructive pulmonary disease (COPD) or no COPD. Lung cancer prevalence, incidence, histology, and stage shift were compared after stratification by COPD. MEASUREMENTS AND MAIN RESULTS: For screening participants with spirometric COPD (n = 6,436), there was a twofold increase in lung cancer incidence (incident rate ratio, 2.15; P < 0.001) and, when compared according to screening arm, no excess lung cancers and comparable histology. Compared with chest radiography, there was also a trend favoring reduced late-stage and increased early-stage cancers in the CT arm (P = 0.054). For those with normal baseline spirometry (n = 12,039), we found an excess of lung cancers during screening in the CT arm, almost exclusively early-stage adenocarcinoma-related cancers (histology shift and overdiagnosis). After correction for these excess cancers, stage shift was marginal (P = 0.077). CONCLUSIONS: In the CT arm of the NLST-ACRIN (American College of Radiology Imaging Network) cohort, COPD status was associated with a doubling of lung cancer incidence, no apparent overdiagnosis, and a more favorable stage shift.

Feasibility of precision smoking treatment in a low-income community setting: results of a pilot randomized controlled trial in The Southern Community Cohort Study.

BACKGROUND: The feasibility of precision smoking treatment in socioeconomically disadvantaged communities has not been studied. METHODS: Participants in the Southern Community Cohort Study who smoked daily were invited to join a pilot randomized controlled trial of three smoking cessation interventions: guideline-based care (GBC), GBC plus nicotine metabolism-informed care (MIC), and GBC plus counseling guided by a polygenic risk score (PRS) for lung cancer. Feasibility was assessed by rates of study enrollment, engagement, and retention, targeting > 70% for each. Using logistic regression, we also assessed whether feasibility varied by age, sex, race, income, education, and attitudes toward precision smoking treatment. RESULTS: Of 92 eligible individuals (79.3% Black; 68.2% with household income < $15,000), 67 (72.8%; 95% CI 63.0-80.9%) enrolled and were randomized. Of these, 58 (86.6%; 95% CI 76.4-92.8%) engaged with the intervention, and of these engaged participants, 43 (74.1%; 95% CI 61.6-83.7%) were retained at 6-month follow-up. Conditional on enrollment, older age was associated with lower engagement (OR 0.83, 95% CI 0.73-0.95, p = 0.008). Conditional on engagement, retention was significantly lower in the PRS arm than in the GBC arm (OR 0.18, 95% CI 0.03-1.00, p = 0.050). No other selection effects were observed. CONCLUSIONS: Genetically informed precision smoking cessation interventions are feasible in socioeconomically disadvantaged communities, exhibiting high enrollment, engagement, and retention irrespective of race, sex, income, education, or attitudes toward precision smoking treatment. Future smoking cessation interventions in this population should take steps to engage older people and to sustain participation in interventions that include genetic risk counseling. TRIAL REGISTRATION: ClinicalTrials.gov No. NCT03521141, Registered 27 April 2018, https://www. CLINICALTRIALS: gov/study/NCT03521141.

Invitation methods for Indigenous New Zealand Maori in lung cancer screening: Protocol for a pragmatic cluster randomized controlled trial.

Lung cancer screening can significantly reduce mortality from lung cancer. Further evidence about how to optimize lung cancer screening for specific populations, including Aotearoa New Zealand (NZ)'s Indigenous Maori (who experience disproportionately higher rates of lung cancer), is needed to ensure it is equitable. This community-based, pragmatic cluster randomized trial aims to determine whether a lung cancer screening invitation from a patient's primary care physician, compared to from a centralized screening service, will optimize screening uptake for Maori. Participating primary care practices (clinics) in Auckland, Aotearoa NZ will be randomized to either the primary care-led or centralized service for delivery of the screening invitation. Clinic patients who meet the following criteria will be eligible: Maori; aged 55-74 years; enrolled in participating clinics in the region; ever-smokers; and have at least a 2% risk of developing lung cancer within six years (determined using the PLCOM2012 risk prediction model). Eligible patients who respond positively to the invitation will undertake shared decision-making with a nurse about undergoing a low dose CT scan (LDCT) and an assessment for Chronic Obstructive Pulmonary Disease (COPD). The primary outcomes are: 1) the proportion of eligible population who complete a risk assessment and 2) the proportion of people eligible for a CT scan who complete the CT scan. Secondary outcomes include evaluating the contextual factors needed to inform the screening process, such as including assessment for Chronic Obstructive Pulmonary Disease (COPD). We will also use the RE-AIM framework to evaluate specific implementation factors. This study is a world-first, Indigenous-led lung cancer screening trial for Maori participants. The study will provide policy-relevant information on a key policy parameter, invitation method. In addition, the trial includes a nested analysis of COPD in the screened Indigenous population, and it provides baseline (T0 screen round) data using RE-AIM implementation outcomes.

Prevalence of asthma and atopy in sarcoidosis.

BACKGROUND AND OBJECTIVE: We hypothesized that the prevalence of allergic disorders, characterized by the release of type 2 cytokines (IL-4, IL-5, IL-10), would be lower in sarcoidosis in which there is a dominant type 1 immune response (IL-2, interferon-gamma). The objective was to measure the prevalence of atopy and self-reported asthma in patients with sarcoidosis. METHODS: Sarcoidosis patients (n = 136, 72 M, age range 22-75), recruited in the outpatient setting, completed a modified European Community Respiratory Health Survey. 123 of these patients provided blood for allergy testing. RESULTS: For the cohort as a whole the self-reported prevalence of asthma ever (21.5%) and asthma attack in the last 12 months (7.5%), was high as was wheezing (42.1%), breathlessness with wheeze (22.3%) and use of an asthma medication (13.1%). The prevalence of atopy was 34%. These data are not different from the previously reported prevalence of asthma and atopy in New Zealand. CONCLUSIONS: The same prevalence of asthma symptoms and atopy as in the normal population suggests that the immune system is not skewed away from mounting T helper type 2 immune responses in sarcoidosis.

The six-minute walk test using forehead oximetry is reliable in the assessment of scleroderma lung disease.

BACKGROUND AND OBJECTIVE: The six-minute walk test (6MWT) is a validated field test in the assessment of interstitial lung disease but may not be so useful in scleroderma (SSc) lung disease. The aim of this study was to determine the reliability of the 6MWT in patients with SSc and correlate results with morphological and functional measures of disease severity. METHODS: Thirty patients (24 female, mean age 47, mean diffusing capacity of carbon monoxide 65%, vital capacity 77% predicted) with American College of Rheumatology classification of SSc performed two 6MWT using various oximetry sites, 1 week apart, and underwent SSc-specific disease severity and quality-of-life measurements, lung function, high-resolution computed tomography and echocardiography. RESULTS: There was good reliability between the two 6MWT (distance; intraclass correlation coefficient 0.95, r = 0.89, Borg; intraclass correlation coefficient 0.85, r = 0.91, both P < 0.00 for r), and Bland Altman plots demonstrate good agreement between measures 1 week apart. Forehead and finger oximetry were more reliable than earlobe (intraclass correlation coefficient 0.64, 0.60, 0.24; r = 0.46, 0.47, 0.14; n = 22, 17, 7, respectively). Forehead desaturation correlated with forced expiratory volume in 1 s (r = 0.55, P = 0.01) and forced vital capacity (r = 0.59, P = 0.01). Distance correlated with all physiological measures: forced expiratory volume in 1 s (r = 0.55, P = 0.01), forced vital capacity (r = 0.61, P = 0.01) and diffusing capacity of carbon monoxide (r = 0.42, P = 0.05). Computed tomography extent and patterns of disease correlated poorly with 6MWT measures, and global measures of SSc correlated only with post-test Borg score. CONCLUSIONS: The 6MWT is feasible and reliable in SSc lung disease, but forehead oximetry should be used. The test measurements correlate reasonably but variably with functional and morphological measures of disease severity.

Statin use in COPD patients is associated with a reduction in mortality: a national cohort study.

AIMS: To assess whether statin use is associated with reduced mortality in patients with chronic obstructive pulmonary disease (COPD). METHODS: Hospitalisation, drug dispensing, and mortality records were linked for New Zealanders aged 50-80 years discharged from hospital with a first admission with COPD in 2006. Patients were classified according to whether or not they were prescribed statins prior to admission. Baseline characteristics were compared and hazard ratios calculated for statin users versus statin non-users for all-cause mortality over follow-up of up to 4 years. RESULTS: A total of 1,687 patients (mean age 70.6 years) were followed, including 596 statin users and 1,091 non-users. There were more men in the statin user group (58.4% vs. 48.5%), and statin users were more likely to have a history of cardiovascular disease (58.6% vs. 25.1%), prescription for frusemide as a proxy for heart failure (47.7% vs. 24.5%) or diabetes (35.4% vs.11.6%) than statin non-users (p<0.001). A total of 671 deaths occurred during the follow-up period. After adjustment for age, sex, ethnic group, history of cardiovascular disease, diabetes, and prescription for frusemide, the hazard ratio for statin users vs. statin non-users for all-cause mortality was 0.69 (95% CI 0.58 to 0.84). CONCLUSIONS: Statin use is associated with a 30% reduction in all-cause mortality at 3-4 years after first admission for COPD, irrespective of a past history of cardiovascular disease and diabetes.

How the genetics of lung cancer may overlap with COPD.

Over the last 30years, epidemiological studies have shown that COPD is the single most important risk factor for lung cancer after smoking exposure. Recent genetic studies using genome-wide approaches suggest that the genetic risk factors predisposing smokers to COPD and lung cancer may overlap. The genes identified by these studies suggest that this overlapping genetic susceptibility may be mediated through receptors expressed on the bronchial epithelium that implicate molecular pathways underlying both COPD and lung cancer. Furthermore, it appears that aberrant inflammatory and/or immune-modulatory pathways leading to excess matrix metalloproteinases, growth factors and airway remodelling in COPD may also be promoting malignant transformation of the bronchial epithelium. The process linking inflammation, remodelling and cancer formation is called epithelial-mesenchymal transition. There are several clinical implications arising from the COPD-lung cancer overlap. First, if COPD is a precursor disease to lung cancer then efforts to prevent COPD, might be even more important. Second, if drugs targeting the overlapping molecular pathways can be identified, chemoprevention that reduce the propensity to COPD and lung cancer is an attractive option. Finally, if low-dose computerized tomography can identify treatable lung cancer, gene-based tests of susceptibility might help identify those smokers who should undergo radiological screening.

Smoking cessation: the potential role of risk assessment tools as motivational triggers.

Smoking is the most important and preventable cause of morbidity and premature mortality in developed and developing countries. To date, efforts to reduce the burden of smoking have focused on non-personalised strategies. Anxiety about ill health, especially lung cancer and emphysema, is the foremost concern for smokers and a major reason for quitting. Recent efforts in cessation management focus on behaviour change and pharmacotherapy. The '3 Ts' (tension, trigger, treatment) model of behaviour change proposes that at any one time a smoker experiences varying degrees of motivational tension, which in the presence of a trigger may initiate or enhance quitting. Smokers' optimistic bias (ie, denial of one's own vulnerability) sustains continued smoking, while increasing motivational tension (eg, illness) favours quitting. The 1 year quit rates achieved when smokers encounter a life threatening event, such as a heart attack or lung cancer, are as much as 50-60%. Utilising tests of lung function and/or genetic susceptibility personalises the risk and have been reported to achieve 1 year quit rates of 25%. This is comparable to quit rates achieved among healthy motivated smokers using smoking cessation drug therapy. In this paper we review existing evidence and propose that identifying those smokers at increased risk of an adverse smoking related disease may be a useful motivational tool, and enhance existing public health strategies directed at smoking cessation.