Metallomic Signatures of Lung Cancer and Chronic Obstructive Pulmonary Disease.

Lung cancer (LC) is the leading cause of cancer deaths, and chronic obstructive pulmonary disease (COPD) can increase LC risk. Metallomics may provide insights into both of these tobacco-related diseases and their shared etiology. We conducted an observational study of 191 human serum samples, including those of healthy controls, LC patients, COPD patients, and patients with both COPD and LC. We found 18 elements (V, Al, As, Mn, Co, Cu, Zn, Cd, Se, W, Mo, Sb, Pb, Tl, Cr, Mg, Ni, and U) in these samples. In addition, we evaluated the elemental profiles of COPD cases of varying severity. The ratios and associations between the elements were also studied as possible signatures of the diseases. COPD severity and LC have a significant impact on the elemental composition of human serum. The severity of COPD was found to reduce the serum concentrations of As, Cd, and Tl and increased the serum concentrations of Mn and Sb compared with healthy control samples, while LC was found to increase Al, As, Mn, and Pb concentrations. This study provides new insights into the effects of LC and COPD on the human serum elemental profile that will pave the way for the potential use of elements as biomarkers for diagnosis and prognosis. It also sheds light on the potential link between the two diseases, i.e., the evolution of COPD to LC.

Clinical and functional characteristics of individuals with alpha-1 antitrypsin deficiency: EARCO international registry.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a rare disease that is associated with an increased risk of pulmonary emphysema. The European AATD Research Collaboration (EARCO) international registry was founded with the objective of characterising the individuals with AATD and investigating their natural history. METHODS: The EARCO registry is an international, observational and prospective study of individuals with AATD, defined as AAT serum levels < 11 µM and/or proteinase inhibitor genotypes PI*ZZ, PI*SZ and compound heterozygotes or homozygotes of other rare deficient variants. We describe the characteristics of the individuals included from February 2020 to May 2022. RESULTS: A total of 1044 individuals from 15 countries were analysed. The most frequent genotype was PI*ZZ (60.2%), followed by PI*SZ (29.2%). Among PI*ZZ patients, emphysema was the most frequent lung disease (57.2%) followed by COPD (57.2%) and bronchiectasis (22%). Up to 76.4% had concordant values of FEV1(%) and KCO(%). Those with impairment in FEV1(%) alone had more frequently bronchiectasis and asthma and those with impairment in KCO(%) alone had more frequent emphysema and liver disease. Multivariate analysis showed that advanced age, male sex, exacerbations, increased blood platelets and neutrophils, augmentation and lower AAT serum levels were associated with worse FEV1(%). CONCLUSIONS: EARCO has recruited > 1000 individuals with AATD from 15 countries in its first 2 years. Baseline cross sectional data provide relevant information about the clinical phenotypes of the disease, the patterns of functional impairment and factors associated with poor lung function. Trial registration www. CLINICALTRIALS: gov (ID: NCT04180319).

Estimated Prevalence and Number of PiMZ Genotypes of Alpha-1 Antitrypsin in Seventy-Four Countries Worldwide.

BACKGROUND: The α-1 antitrypsin (AAT) protease inhibitor PiMZ is a moderately deficient genotype, until recently considered of little or negligible risk. However, a growing number of studies show that MZ carriers have an increased risk of developing lung and liver diseases, if exposed to smoking or other airborne or industrial pollutants, and hepatotoxic substances. METHODS: We used the epidemiological studies performed to determine the frequencies of PiM and PiZ worldwide, based on the following criteria: 1) samples representative of the general population; 2) AAT phenotyping or genotyping characterized by adequate methods, including isoelectric focusing and polymerase chain reaction; and 3) studies with reliable results assessed with a coefficient of variation calculated from the sample size and 95% confidence intervals, to measure the precision of the results in terms of dispersion of the data around the mean. RESULTS: The present review reveals an impressive number of MZs of more than 35 million in 74 countries of the world with available data. Seventy-five percent of them are people of Caucasian European heritage, mostly living in Europe, America, Australia and New Zealand. Twenty percent of the remaining MZs live in Asia, with the highest concentrations in the Middle East, Eastern¸ Southern, and South-eastern regions of the Asian continent. The remaining five percent are Africans residing in Western and Eastern Africa. CONCLUSION: Considering the high rate of smoking, the outdoor and the indoor air pollution from solid fuels used in cooking and heating, and the exposure to industrial dusts and chemicals in many of these countries, these figures are very worrying, and hence the importance of adequately assessing MZ subjects, recommending them rigorous preventive measures based on the adoption of healthy lifestyles, including avoidance of smoking and alcohol.

Natural Course of the Diffusing Capacity of the Lungs for Carbon Monoxide in COPD: Importance of Sex.

BACKGROUND: The value of the single-breath diffusing capacity of the lungs for carbon monoxide (Dlco) relates to outcomes for patients with COPD. However, little is known about the natural course of Dlco over time, intersubject variability, and factors that may influence Dlco progression. RESEARCH QUESTION: What is the natural course of Dlco in patients with COPD over time, and which other factors, including sex differences, could influence this progression? STUDY DESIGN AND METHODS: We phenotyped 602 smokers (women, 33%), of whom 506 (84%) had COPD and 96 (16%) had no airflow limitation. Lung function, including Dlco, was monitored annually over 5 years. A random coefficients model was used to evaluate Dlco changes over time. RESULTS: The mean (± SE) yearly decline in Dlco % in patients with COPD was 1.34% ± 0.015%/y. This was steeper compared with non-COPD control subjects (0.04% ± 0.032%/y; P = .004). Sixteen percent of the patients with COPD, vs 4.3% of the control subjects, had a statistically significant Dlco % slope annual decline (4.14%/y). At baseline, women with COPD had lower Dlco values (11.37% ± 2.27%; P < .001) in spite of a higher FEV1 % than men. Compared with men, women with COPD had a steeper Dlco annual decline of 0.89% ± 0.42%/y (P = .039). INTERPRETATION: Patients with COPD have an accelerated decline in Dlco compared with smokers without the disease. However, the decline is slow, and a testing interval of 3 to 4 years may be clinically informative. The lower and more rapid decline in Dlco values in women, compared with men, suggests a differential impact of sex in gas exchange function. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01122758; URL: www.clinicaltrials.gov.

Determinants of the Appearance and Progression of Early-Onset Chronic Obstructive Pulmonary Disease in Young Adults. A Case-Control Study with Follow-up. / EARLY COPD: determinantes de la aparición y progresión de la enfermedad pulmonar obstructiva crónica en adultos jóvenes. Protocolo de un estudio caso-control con seguimiento.

INTRODUCTION AND OBJECTIVES: Determinants of chronic obstructive pulmonary disease (COPD) in the early stages of its natural history are not well known. Improving our knowledge of these factors will help to design interventions that can modify prognosis. Study objectives are: a) to characterize a COPD population of young adults aged 35-50 years from a multidimensional point of view; b) to compare these patients with smokers with normal lung function; and c) to create a cohort of young adults aged 35-50 years (smokers or former smokers), with and without COPD, who will be followed in the future to improve understanding of the natural history of the disease. PARTICIPANTS AND METHOD: This is a case-control multicenter study aimed at establishing a well-characterized cohort of young adults, smokers or former-smokers, with and without COPD, for subsequent follow-up. A total of 311 participants (101 cases and 210 controls) were selected from approximately 30 primary care settings and 12 hospitals in 8 Spanish regions. Subjects were smokers or former smokers (>10 pack-years) aged 35-50 years. Diagnosis of COPD was based on a post-bronchodilator result of FEV1/FVC<70%. The main study variables were: questionnaires on health, symptoms, exacerbations and daily physical activity, lung function tests, blood and sputum samples, and low-dose computed tomography. In the statistical analysis, COPD patient characteristics will be described and compared with control subjects using a logistic regression analysis.

Changes and Clinical Consequences of Smoking Cessation in Patients With COPD: A Prospective Analysis From the CHAIN Cohort.

BACKGROUND: Despite the existing evidence-based smoking cessation interventions, chances of achieving that goal in real life are still low among patients with COPD. We sought to evaluate the clinical consequences of changes in smoking habits in a large cohort of patients with COPD. METHODS: CHAIN (COPD History Assessment in Spain) is a Spanish multicenter study carried out at pulmonary clinics including active and former smokers with COPD. Smoking status was certified by clinical history and co-oximetry. Clinical presentation and disease impact were recorded via validated questionnaires, including the London Chest Activity of Daily Living (LCADL) and the Hospital Anxiety and Depression Scale (HADS). No specific smoking cessation intervention was carried out. Factors associated with and clinical consequences of smoking cessation were analyzed by multivariate regression and decision tree analyses. RESULTS: One thousand and eighty-one patients with COPD were included (male, 80.8%; age, 65.2 [SD 8.9] years; FEV1, 60.2 [20.5]%). During the 2-year follow-up time (visit 2, 906 patients; visit 3, 791 patients), the majority of patients maintained the same smoking habit. Decision tree analysis detected chronic expectoration as the most relevant variable to identify persistent quitters in the future, followed by an LCADL questionnaire (cutoff 9 points). Total anxiety HADS score was the most relevant clinical impact associated with giving up tobacco, followed by the LCADL questionnaire with a cutoff value of 10 points. CONCLUSIONS: In this real-life prospective COPD cohort with no specific antismoking intervention, the majority of patients did not change their smoking status. Our study also identifies baseline expectoration, anxiety, and dyspnea with daily activities as the major determinants of smoking status in COPD. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT01122758; URL: www.clinicaltrials.gov.

The importance of symptoms in the longitudinal variability of clusters in COPD patients: A validation study.

BACKGROUND AND OBJECTIVE: Cluster analysis has been utilized to explore phenotypic heterogeneity in chronic obstructive pulmonary disease (COPD). To date, little is known about the longitudinal variability of clusters in COPD patients. We aimed to evaluate the 2-year cluster variability in stable COPD patients. METHODS: We evaluated the following variables in COPD patients at baseline and 2 years later: age, gender, pack-year history, body mass index (BMI), modified Medical Research Council (MMRC) scale, 6-min walking distance (6MWD), spirometry and COPD Assessment Test (CAT). Patient classification was performed using cluster analysis at baseline and 2 years later. Each patient's cluster variability after 2 years and its parameters associated with cluster change were explored. RESULTS: A total of 521 smokers with COPD were evaluated at baseline and 2 years later. Three different clusters were consistently identified at both evaluation times: cluster A (of younger age, mild airway limitation, few symptoms), cluster B (intermediate) and cluster C (of older age, severe airway limitation and highly symptomatic). Two years later, 70% of patients were unchanged, whereas 30% changed from one cluster to another: 20% from A to B; 15% from B to A; 15% from B to C; 42% from C to B and 8% from C to A. 6MWD, forced expiratory volume in 1 s (FEV1 ) % and CAT were the principal parameters responsible for this change. CONCLUSION: After 2 years of follow-up, most of the COPD patients maintained their cluster assignment. Exercise tolerance, lung function and quality of life were the main driving parameters in those who change their cluster assignment.

Recommendations for the Diagnosis and Management of Asbestos-Related Pleural and Pulmonary Disease. / Recomendaciones sobre el diagnóstico y manejo de la enfermedad pleural y pulmonar por asbesto.

Asbestos is the term used for a set of mineral silicates that tend to break up into fibers. Its use has been associated with numerous diseases affecting the lung and pleura in particular, all of which are characterized by their long period of latency. Asbestos, moreover, has been recognized by the WHO as a Group IA carcinogen since 1987 and its use was banned in Spain in 2002. The publication in 2013 of the 3rd edition of the specific asbestos health monitoring protocol, together with the development of new diagnostic techniques, prompted the SEPAR EROM group to sponsor publication of guidelines, which review the clinical, radiological and functional aspects of the different asbestos-related diseases. Recommendations have also been made for the diagnosis and follow-up of exposed patients. These recommendations were drawn up in accordance with the GRADE classification system.

Defining the Asthma-COPD Overlap Syndrome in a COPD Cohort.

BACKGROUND: Asthma-COPD overlap syndrome (ACOS) has been recently described by international guidelines. A stepwise approach to diagnosis using usual features of both diseases is recommended although its clinical application is difficult. METHODS: To identify patients with ACOS, a cohort of well-characterized patients with COPD and up to 1 year of follow-up was analyzed. We evaluated the presence of specific characteristics associated with asthma in this COPD cohort, divided into major criteria (bronchodilator test > 400 mL and 15% and past medical history of asthma) and minor criteria (blood eosinophils > 5%, IgE > 100 IU/mL, or two separate bronchodilator tests > 200 mL and 12%). We defined ACOS by the presence of one major criterion or two minor criteria. Baseline characteristics, health status (COPD Assessment Test [CAT]), BMI, airflow obstruction, dyspnea, and exercise capacity (BODE) index, rate of exacerbations, and mortality up to 1 year of follow-up were compared between patients with and without criteria for ACOS. RESULTS: Of 831 patients with COPD included,125 (15%) fulfilled the criteria for ACOS, and 98.4% of them sustained these criteria after 1 year. Patients with ACOS were predominantly male (81.6%), with symptomatic mild to moderate disease (67%), who were receiving inhaled corticosteroids (63.2%). There were no significant differences in baseline characteristics, and only survival was worse in patients with non-ACOS COPD after 1 year of follow-up (P < .05). CONCLUSIONS: The proposed ACOS criteria are present in 15% of a cohort of patients with COPD and these patients show better 1-year prognosis than clinically similar patients with COPD with no ACOS criteria. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01122758; URL: www.clinicaltrials.gov.

Elevated carboxyhemoglobin: sources of carbon monoxide exposure.

INTRODUCTION: Inhalation of carbon monoxide (CO) can result in poisoning, with symptoms ranging from mild and nonspecific to severe, or even death. CO poisoning is often underdiagnosed because exposure to low concentrations goes unnoticed, and threshold values for normal carboxyhemoglobin vary according to different authors. The aim of our study was to analyze carboxyhemoglobin (COHb) levels in an unselected population and detect sources of CO exposure METHODS: In a cross-sectional descriptive study, we analyzed consecutive arterial blood gas levels processed in our laboratory. We selected those with COHb≥2.5% in nonsmokers and ≥5% in smokers. In these cases a structured telephone interview was conducted. RESULTS: Elevated levels of COHb were found in 64 (20%) of 306 initial determinations. Of these, data from 51 subjects aged 65±12 years, 31 (60%) of which were men, were obtained. Mean COHb was 4.0%. Forty patients (78%) were non-smokers with mean COHb of 3.2%, and 11 were smokers with COHb of 6.7%. In 45 patients (88.2%) we detected exposure to at least one source of ambient CO other than cigarette smoke. CONCLUSIONS: A significant proportion of individuals from an unselected sample had elevated levels of COHb. The main sources of CO exposure were probably the home, so this possibility should be explored. The population should be warned about the risks and encouraged to take preventive measures.

Clinical application of the COPD assessment test: longitudinal data from the COPD History Assessment in Spain (CHAIN) cohort.

OBJECTIVE: The COPD Assessment Test (CAT) has been proposed for assessing health status in COPD, but little is known about its longitudinal changes. The objective of this study was to evaluate 1-year CAT variability in patients with stable COPD and to relate its variations to changes in other disease markers. METHODS: We evaluated the following variables in smokers with and without COPD at baseline and after 1 year: CAT score, age, sex, smoking status, pack-year history, BMI, modified Medical Research Council (mMRC) scale, 6-min walk distance (6MWD), lung function, BODE (BMI, obstruction, dyspnea, exercise capacity) index, hospital admissions, Hospital and Depression Scale, and the Charlson comorbidity index. In patients with COPD, we explored the association of CAT scores and 1-year changes in the studied parameters. RESULTS: A total of 824 smokers with COPD and 126 without COPD were evaluated at baseline and 441 smokers with COPD and 66 without COPD 1 year later. At 1 year, CAT scores for patients with COPD were similar (± 4 points) in 56%, higher in 27%, and lower in 17%. Of note, mMRC scale scores were similar (± 1 point) in 46% of patients, worse in 36%, and better in 18% at 1 year. One-year CAT changes were best predicted by changes in mMRC scale scores (ß-coefficient, 0.47; P < .001). Similar results were found for CAT and mMRC scale score in smokers without COPD. CONCLUSIONS: One-year longitudinal data show variability in CAT scores among patients with stable COPD similar to mMRC scale score, which is the best predictor of 1-year CAT changes. Further longitudinal studies should confirm long-term CAT variability and its clinical applicability. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01122758; URL: www.clinicaltrials.gov.

Recommendations for fitness for work medical evaluations in chronic respiratory patients. Spanish Society of Pulmonology and Thoracic Surgery (SEPAR).

Chronic respiratory diseases often cause impairment in the functions and/or structure of the respiratory system, and impose limitations on different activities in the lives of persons who suffer them. In younger patients with an active working life, these limitations can cause problems in carrying out their normal work. Article 41 of the Spanish Constitution states that «the public authorities shall maintain a public Social Security system for all citizens guaranteeing adequate social assistance and benefits in situations of hardship¼. Within this framework is the assessment of fitness for work, as a dual-nature process (medico-legal) that aims to determine whether it is appropriate or not to recognise a person's right to receive benefits which replace the income that they no longer receive as they cannot carry out their work, due to loss of health. The role of the pulmonologist is essential in evaluating the diagnosis, treatment, prognosis and functional capacity of respiratory patients. These recommendations seek to bring the complex setting of fitness for work evaluation to pulmonologists and thoracic surgeons, providing action guidelines that allow them to advise their own patients about their incorporation into working life.

Exposure to residential radon and lung cancer in never-smokers: the preliminary results of the LCRINS study.

INTRODUCTION AND OBJECTIVE: Residential radon is the second most important risk factor for lung cancer and the first among never-smokers. The objective of this study is to report the concentrations of residential radon in a series of never-smoker cases recruited in a multicenter study of cases and controls in northwestern Spain. In this study, all the hospitals in the Spanish province of Galicia and one from Asturias participated. PATIENTS AND METHODS: The present article includes a series of cases with residential radon measurements. All the subjects were personally interviewed, 3 ml of blood were taken from each, and they were each given instructions about how to place a residential radon detector in their homes. RESULTS: Sixty-nine case subjects were recruited, 84% of whom were women with a mean age of 71, and 81% of whom had adenocarcinoma. The average concentration of residential radon in the cases was 237 Bq/m(3), while the average concentration in the Galician population is 79 Bq/m(3). No relationship was observed between the concentration of residential radon and either sex or age at the time of diagnosis of the cases, but there was a tendency towards having a greater concentration in those diagnosed with small-cell and large-cell carcinoma. CONCLUSIONS: The concentrations of residential radon in the cases included are very high at about three times the average concentration of residential radon to which the general population of Galicia is exposed.

[The air belongs to us: the importance of maintaining air quality]. / El aire es nuestro: la importancia de mantener su calidad.

Interest in identifying the long-term harmful effects of atmospheric pollution on respiratory health, and concern about this issue, has prompted several studies, whose results have been published throughout this year. On the occasion of the Spanish Society of Pneumology and Thoracic Surgery's Year of the Environment, from the Section of Occupational and Environmental Respiratory Diseases, we review the advances made in the effects of atmospheric pollution on respiratory health and the actions undertaken by the Society. The main objective of the Society's Year of the Environment is to inform citizens in general and respiratory patients in particular of the benefits of breathing clean air. The first step in achieving this aim is education. The goal is to educate young people in lasting habits that promote a respectful attitude to the environment, inculcating them with the need for sustainable development through responsible energy consumption and reduction of the emission of pollutants. Informed citizens will demand public health policies aimed at maintaining the quality of the air we breathe from politicians. The website www.elaireesnuestro.com provides information and educational material on the subject.

[Update in respiratory disease and environmental exposure: an invisible relationship]. / Actualización en enfermedad respiratoria y exposición ambiental: una relación invisible.

Significant contributions have been made in the past year on different aspects of occupational/environmental respiratory disease. In the case of neoplastic diseases associated with asbestos inhalation, the areas of most interest have been in the search for tumour markers, the importance of the determination of asbestos fibre deposits in biological samples, and new therapeutic schemes in malignant pleural mesothelioma. A consensus article has been published on occupational asthma, in which some clinical evidenced-based recommendations are established, directed at the diagnosis and management of work-related asthma. As regards hypersensitivity-induced pneumonitis, the clinical and evolutionary aspects of this disease have been described in a large series of 86 patients with pigeon-fancier lung. There have also been interesting studies published this year that emphasise the need to take an occupational history in patients with respiratory symptoms in order to look for a causal or synergic relationship with smoking. Finally, the results of studies have been published which were directed at elucidating the role of urban contamination, mainly caused by road traffic, in the deterioration of lung function. A recent study showed that it would be possible to achieve a significant reduction in urban mortality attributed to urban contamination by reducing the levels of PM 2.5. They conclude that more restrictive standards need to be adopted in Europe to protect the health of the population, which coincides with the proposal by the World Health Organisation.

Respiratory disease in a cohort of 2,579 coal miners followed up over a 20-year period.

INTRODUCTION: Working in coal mines is a risk factor for pneumoconiosis and COPD. There still exist, however, doubts and debates about the risk involved in such work for tuberculosis and lung cancer. The aim of this study was to clarify some of these uncertainties through the study of a cohort group. METHODS: The cohort comprises 2,579 miners. An initial medical examination was carried out when they began to work in the mine, and three further examinations were performed over the 20 years of the study. The follow-up failure rate was 23.7%. RESULTS: Ninety-nine workers (3.8%) developed round opacities (category 1) that were significantly related to the kind of work in a crude analysis (p = 0.045), with a greater frequency (7.3%) among rock workers, who have greater exposure to silica, and were almost significantly related to tobacco use (p = 0.092). These round opacities also show a significant relation to smoking, being more frequent (4.9%) among smokers, both in the crude analysis (p = 0.028) and in the multivariable analysis (p = 0.001) controlling for rock work. In 240 workers (12.7%), accelerated FEV(1) decreases were observed with significant relations to tobacco use (p = 0.001) and rock work (p = 0.044). Pulmonary tuberculosis was diagnosed in four cases, with an incidence of eight in 10(5) person-years. This rate falls within the limits expected for the region. No case of lung cancer was observed. CONCLUSION: In summary, our results showed the following: round opacities (category 1) were related to smoking and, probably, to rock work; accelerated FEV(1) decreases were related to rock work and tobacco consumption. There was no identified increase in tuberculosis or lung cancer in this cohort.