Comorbid conditions as predictors of mortality in severe COPD - an eight-year follow-up cohort study.

Purpose: Co-morbidities are common in chronic obstructive pulmonary disease (COPD) and are associated with increased morbidity and mortality. The aim of the present study was to explore the prevalence of several comorbid conditions in severe COPD, and to investigate and compare their associations with long-term mortality. Methods: In May 2011 to March 2012, 241 patients with COPD stage 3 or 4 were included in the study. Information was collected on sex, age, smoking history, weight and height, current pharmacological treatment, number of exacerbations the recent year and comorbid conditions. At December 31st, 2019, mortality data (all-cause and cause specific) were collected from the National Cause of Death Register. Data were analyzed using Cox-regression analysis with gender, age, previously established predictors of mortality and comorbid conditions as independent variables, and all-cause mortality and cardiac and respiratory mortality, respectively, as dependent variables. Results: Out of 241 patients, 155 (64%) were deceased at the end of the study period; 103 patients (66%) died of respiratory disease and 25 (16%) of cardiovascular disease. Impaired kidney function was the only comorbid condition independently associated with increased all-cause mortality (HR (95% CI) 3.41 (1.47-7.93) p=0.004) and respiratory mortality (HR (95%CI) 4.63 (1.61 to 13.4), p = 0.005). In addition, age ≥70, BMI <22 and lower FEV1 expressed as %predicted were significantly associated with increased all-cause and respiratory mortality. Conclusion: In addition to the risk factors high age, low BMI and poor lung function; impaired kidney function appears to be an important risk factor for mortality in the long term, which should be taken into account in the medical care of patients with severe COPD.

Diagnostic approach to lower airway dysfunction in athletes: a systematic review and meta-analysis by a subgroup of the IOC consensus on 'acute respiratory illness in the athlete'.

OBJECTIVES: To compare the performance of various diagnostic bronchoprovocation tests (BPT) in the assessment of lower airway dysfunction (LAD) in athletes and inform best clinical practice. DESIGN: Systematic review with sensitivity and specificity meta-analyses. DATA SOURCES: PubMed, EBSCOhost and Web of Science (1 January 1990-31 December 2021). ELIGIBILITY CRITERIA: Original full-text studies, including athletes/physically active individuals (15-65 years) who underwent assessment for LAD by symptom-based questionnaires/history and/or direct and/or indirect BPTs. RESULTS: In 26 studies containing data for quantitative meta-analyses on BPT diagnostic performance (n=2624 participants; 33% female); 22% had physician diagnosed asthma and 51% reported LAD symptoms. In athletes with symptoms of LAD, eucapnic voluntary hyperpnoea (EVH) and exercise challenge tests (ECTs) confirmed the diagnosis with a 46% sensitivity and 74% specificity, and 51% sensitivity and 84% specificity, respectively, while methacholine BPTs were 55% sensitive and 56% specific. If EVH was the reference standard, the presence of LAD symptoms was 78% sensitive and 45% specific for a positive EVH, while ECTs were 42% sensitive and 82% specific. If ECTs were the reference standard, the presence of LAD symptoms was 80% sensitive and 56% specific for a positive ECT, while EVH demonstrated 65% sensitivity and 65% specificity for a positive ECT. CONCLUSION: In the assessment of LAD in athletes, EVH and field-based ECTs offer similar and moderate diagnostic test performance. In contrast, methacholine BPTs have lower overall test performance. PROSPERO REGISTRATION NUMBER: CRD42020170915.

[Exercise training can improve dyspnea among persons with COPD and IPF]. / Fysisk aktivitet kan reducera dyspné vid KOL och lungfibros.

This article presents updated data regarding exercise training among persons with chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Persons with stable COPD and IPF can improve quality of life, physical capacity and dyspnea after a period of exercise training. Persons with COPD exacerbation can improve quality of life and physical capacity, and decrease hospital re-admissions, if they start physical activity directly after the exacerbation. Persons with stable COPD and IPF should be recommended aerobic and muscle strengthening  training. For those with balance impairments balance training is also recommended. Persons with COPD exacerbation should be recommended activities of daily living (ADL) followed by muscle strengthening training and then aerobic training in the early recovery phase. Diagnosis-specific advice includes individually tailored exercise training, physical activity recommendations, breathing techniques, and that oxygen saturation during exercise should be ≥88 percent in COPD and ≥85 percent in IPF.

Treatment Patterns, Socioeconomic Status and Clinical Burden in Mild COPD: A Swedish Real-World, Retrospective Cohort Study, the ARCTIC Study.

Background: Patients with mild chronic obstructive pulmonary disease (COPD) account for more than half of the total COPD population but are often undiagnosed and sparsely studied. This real-world, longitudinal study compared the socioeconomic burden, clinical characteristics and treatment patterns in patients with mild COPD and age- and gender-matched controls. Patients and methods: Our population included mild COPD patients (forced expiratory volume in one second ≥80% of predicted value) and reference controls from 52 Swedish primary care centres over 15 years (2000-2014). We linked electronic medical record (EMR) data to Sweden's National Health Registries. The outcomes analyzed were socioeconomic status including annual income from work, presence of comorbidities and the use of medications. Results: 844 patients with mild COPD were included in this study and matched with 844 reference controls. Compared with the reference controls, mild COPD patients had a significantly lower annual income from work (mean difference, men: 12,559€ and women: 7143€) and were significantly less likely to be married or employed. The presence of comorbidities, including cardiovascular disease, anxiety and depression (only women) was significantly higher in mild COPD patients. The use of medications, such as proton pump inhibitors, antidepressants, central painkillers and sleep medications, was significantly higher in the mild COPD group. Conclusion: Mild COPD presents a considerable socioeconomic and clinical burden compared with reference controls The findings suggest that COPD constitutes a condition that influences health status even in mild disease clearly demanding an increased need for early detection and treatment.

Biomarkers, Clinical Course, and Individual Needs in COPD Patients in Primary Care: The Study Protocol of the Stockholm COPD Inflammation Cohort (SCOPIC).

Background: To facilitate effective personalized medicine, primary health care needs better methods of assessing and monitoring chronic obstructive pulmonary disease (COPD). Aim: This cohort study aims to investigate how biomarkers relate to clinical characteristics and COPD patients' subjective needs over time. Methods: Patients (n=750) in different COPD severity according to the GOLD criteria and age- and sex-matched controls (n=750) will be recruited over a period of 5 years from 15 primary health care centers in Region Stockholm, Sweden, and followed for 10 years in the first instance. Data on patients' subjective needs will be collected via telephone/email, data on clinical/physiological variables (eg, symptoms, exacerbations, comorbidities, medications, smoking habits, lung function) from existing databases that are based on medical records, and data on biomarkers via repeated blood sampling. Quantitative and qualitative methods will be used. Initial results are expected after 2 years (feasibility test), and a larger body of evidence after 5 years. Discussion: The study is expected to provide definitive and clinically useful scientific evidence about how biomarkers relate to clinical variables and patients' subjective needs. This new evidence will facilitate accurate, and personalized COPD management by the use of valid biomarkers. It will provide useful tools for primary care professionals and may facilitate optimal self-management.

[Pharmacological treatment reduces mortality in COPD]. / Behandling med läkemedel kan reducera mortaliteten vid KOL.

Approximately 500 000 individuals in Sweden have chronic obstructive pulmonary disease (COPD). Co-morbid, especially cardiovascular, conditions are common in COPD and globally COPD is the third most common cause of mortality. Mortality in COPD is driven by dyspnea, exacerbations and comorbidities and is reduced by smoking cessation and lung rehabilitation. Also, pharmacological treatment, in particular inhaled corticosteroids, reduces mortality in COPD. The reduction in mortality that can be achieved by treatment with inhaled corticosteroids in combinations with long-acting bronchodilators is of the same order of magnitude as the effect on mortality by treatment of hyperlipidemia and hypertension.

Postnatal growth rate varies with latitude in range-expanding geese: The role of plasticity and day length.

The postnatal growth period is a crucial life stage, with potential lifelong effects on an animal's fitness. How fast animals grow depends on their life-history strategy and rearing environment, and interspecific comparisons generally show higher growth rates at higher latitudes. However, to elucidate the mechanisms behind this gradient in growth rate, intraspecific comparisons are needed. Recently, barnacle geese expanded their Arctic breeding range from the Russian Barents Sea coast southwards, and now also breed along the Baltic and North Sea coasts. Baltic breeders shortened their migration, while barnacle geese breeding along the North Sea stopped migrating entirely. We collected cross-sectional data on gosling tarsus length, head length and body mass, and constructed population-specific growth curves to compare growth rates among three populations (Barents Sea, Baltic Sea and North Sea) spanning 17° in latitude. Growth rate was faster at higher latitudes, and the gradient resembled the latitudinal gradient previously observed in an interspecific comparison of precocial species. Differences in day length among the three breeding regions could largely explain the observed differences in growth rate. In the Baltic, and especially in the Arctic population, growth rate was slower later in the season, most likely because of the stronger seasonal decline in food quality. Our results suggest that differences in postnatal growth rate between the Arctic and temperate populations are mainly a plastic response to local environmental conditions. This plasticity can increase the individuals' ability to cope with annual variation in local conditions, but can also increase the potential to re-distribute and adapt to new breeding environments.

Prevalence of lower airway dysfunction in athletes: a systematic review and meta-analysis by a subgroup of the IOC consensus group on 'acute respiratory illness in the athlete'.

OBJECTIVE: To report the prevalence of lower airway dysfunction in athletes and highlight risk factors and susceptible groups. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, EBSCOhost and Web of Science (1 January 1990 to 31 July 2020). ELIGIBILITY CRITERIA: Original full-text studies, including male or female athletes/physically active individuals/military personnel (aged 15-65 years) who had a prior asthma diagnosis and/or underwent screening for lower airway dysfunction via self-report (ie, patient recall or questionnaires) or objective testing (ie, direct or indirect bronchial provocation challenge). RESULTS: In total, 1284 studies were identified. Of these, 64 studies (n=37 643 athletes) from over 21 countries (81.3% European and North America) were included. The prevalence of lower airway dysfunction was 21.8% (95% CI 18.8% to 25.0%) and has remained stable over the past 30 years. The highest prevalence was observed in elite endurance athletes at 25.1% (95% CI 20.0% to 30.5%) (Q=293, I2=91%), those participating in aquatic (39.9%) (95% CI 23.4% to 57.1%) and winter-based sports (29.5%) (95% CI 22.5% to 36.8%). In studies that employed objective testing, the highest prevalence was observed in studies using direct bronchial provocation (32.8%) (95% CI 19.3% to 47.2%). A high degree of heterogeneity was observed between studies (I2=98%). CONCLUSION: Lower airway dysfunction affects approximately one in five athletes, with the highest prevalence observed in those participating in elite endurance, aquatic and winter-based sporting disciplines. Further longitudinal, multicentre studies addressing causality (ie, training status/dose-response relationship) and evaluating preventative strategies to mitigate against the development of lower airway dysfunction remain an important priority for future research.

COPD - do the right thing.

A gap exists between guidelines and real-world clinical practice for the management and treatment of chronic obstructive pulmonary disease (COPD). Although this has narrowed in the last decade, there is room for improvement in detection rates, treatment choices and disease monitoring. In practical terms, primary care practitioners need to become aware of the huge impact of COPD on patients, have non-judgemental views of smoking and of COPD as a chronic disease, use a holistic consultation approach and actively motivate patients to adhere to treatment.This article is based on discussions at a virtual meeting of leading Nordic experts in COPD (the authors) who were developing an educational programme for COPD primary care in the Nordic region. The article aims to describe the diagnosis and lifelong management cycle of COPD, with a strong focus on providing a hands-on, practical approach for medical professionals to optimise patient outcomes in COPD primary care.

Developing a short-term prediction model for asthma exacerbations from Swedish primary care patients' data using machine learning - Based on the ARCTIC study.

OBJECTIVE: The ability to predict impending asthma exacerbations may allow better utilization of healthcare resources, prevention of hospitalization and improve patient outcomes. We aimed to develop models using machine learning to predict risk of exacerbations. METHODS: Data from 29,396 asthma patients was collected from electronic medical records and national registers covering clinical and epidemiological factors (e.g. comorbidities, health care contacts), between 2000 and 2013. Machine-learning classifiers were used to create models to predict exacerbations within the next 15 days. Model selection was done using the mean cross validation score of area under precision-recall curve (AUPRC). RESULTS: The most important predictors of exacerbation were comorbidity burden and previous exacerbations. Model validation on test data yielded an AUPRC = 0.007 (95% CI: ± 0.0002), indicating that historic clinical information alone may not be sufficient to predict a near future risk of asthma exacerbation. CONCLUSIONS: Supplementation with additional data on environmental triggers, (e.g. weather, pollen count, air quality) and from wearables, might be necessary to improve performance of the short-term predictive model to develop a more clinically useful tool.

Adherence to Treatment Recommendations for Chronic Obstructive Pulmonary Disease - Results from the Swedish National Airway Register.

INTRODUCTION: Swedish guidelines adhere to the international GOLD document regarding management of chronic obstructive pulmonary disease (COPD). Based on data from the Swedish National Airway Register (SNAR) the aim was to evaluate adherence to guidelines of pharmacological treatment of COPD in Swedish primary and secondary care. METHODS: During a period of 18 months, data on symptoms (CAT, mMRC), lung function, exacerbation history and pharmacological treatment from 15,595 COPD patients from 853 primary care and 125 secondary care clinics were collected from SNAR. Patients with a co-diagnosis of asthma were excluded. Patients were divided into four treatment groups: no pharmacological treatment, short-acting bronchodilators alone, long-acting bronchodilators alone and ICS alone or in combination with bronchodilators. RESULTS: Of the patients, 29% were in GOLD group A, 58% in group B, 2% in group C and 11% in group D. CAT score was ≥10 and mMRC score was below 2 in 30.9% of the patients and mMRC score was ≥2 and CAT score <10 in 4.2% of the patients. In 61.4% of the patients, no exacerbation was registered during the last year. Long-acting bronchodilators were prescribed for 78% and ICS for 46% of all patients. In groups A, B, C and D, respectively, 21%, 11%, 11% and 5% did not receive any inhaler therapy; 67%, 81%, 81% and 90% received long-acting bronchodilators; 33%, 46%, 55% and 71% received any ICS containing therapy and 19%, 34%, 39% and 61% received triple therapy. DISCUSSION: Data from the SNAR indicate that only a minority of COPD patients were untreated. There was a liberal use of ICS containing drug combinations in subjects who do not have an indication for ICS. A considerable proportion of subjects at high risk of exacerbations did not receive ICS treatment.

The Impact of Exacerbation Frequency on Clinical and Economic Outcomes in Swedish COPD Patients: The ARCTIC Study.

PURPOSE: The aim of this study was to assess the association between exacerbation frequency and clinical and economic outcomes in patients with COPD. PATIENTS AND METHODS: Electronic medical record data linked to National Health Registries were collected from COPD patients at 52 Swedish primary care centers (2000-2014). The outcomes analyzed were exacerbation rate, mortality, COPD treatments, lung function and healthcare costs during the follow-up period. Based on the exacerbation rate two years before index date, the patients were initially classified into three groups, either 0, 1 or ≥2 exacerbations per year. After the index date, the classification into exacerbation groups was updated each year based on the exacerbation rate during the last year of follow-up. A sensitivity analysis was conducted excluding patients with asthma diagnosis from the analysis. RESULTS: In total 18,586 COPD patients were analyzed. A majority of the patients (60-70%) who either have had no exacerbation or frequent exacerbations (≥2/year) during the pre-index period remained in their group (ie, with 0 or ≥2 annual exacerbations) during up to 11 years of follow-up. Compared with having no exacerbation, mortality was higher in patients having 1 (HR; 2.06 [1.93-2.20]) and ≥2 (4.58 [4.33-4.84]) exacerbations at any time during the follow-up. Lung function decline was more rapid in patients with frequent exacerbations and there was an almost linear relationship between exacerbations frequency and mortality. Total healthcare costs were higher in the frequent exacerbation group (≥2/year) than in patients with no or one exacerbation annually (p<0.0001 for both). The results did not differ from the main analysis after exclusion of patients with a concurrent asthma diagnosis. CONCLUSION: In addition to faster lung function decline and increased mortality, frequent exacerbations in COPD patients imply a significant economic burden.

Predicting Hospitalization Due to COPD Exacerbations in Swedish Primary Care Patients Using Machine Learning - Based on the ARCTIC Study.

PURPOSE: Chronic obstructive pulmonary disease (COPD) exacerbations can negatively impact disease severity, progression, mortality and lead to hospitalizations. We aimed to develop a model that predicts a patient's risk of hospitalization due to severe exacerbations (defined as COPD-related hospitalizations) of COPD, using Swedish patient level data. PATIENTS AND METHODS: Patient level data for 7823 Swedish patients with COPD was collected from electronic medical records (EMRs) and national registries covering healthcare contacts, diagnoses, prescriptions, lab tests, hospitalizations and socioeconomic factors between 2000 and 2013. Models were created using machine-learning methods to predict risk of imminent exacerbation causing patient hospitalization due to COPD within the next 10 days. Exacerbations occurring within this period were considered as one event. Model performance was assessed using the Area under the Precision-Recall Curve (AUPRC). To compare performance with previous similar studies, the Area Under Receiver Operating Curve (AUROC) was also reported. The model with the highest mean cross validation AUPRC was selected as the final model and was in a final step trained on the entire training dataset. RESULTS: The most important factors for predicting severe exacerbations were exacerbations in the previous six months and in whole history, number of COPD-related healthcare contacts and comorbidity burden. Validation on test data yielded an AUROC of 0.86 and AUPRC of 0.08, which was high in comparison to previously published attempts to predict COPD exacerbation. CONCLUSION: Our work suggests that clinically available information on patient history collected via automated retrieval from EMRs and national registries or directly during patient consultation can form the basis for future clinical tools to predict risk of severe COPD exacerbations.

Maternal asthma and early fetal growth, the MAESTRO study.

BACKGROUND: Several maternal conditions can affect fetal growth, and asthma during pregnancy is known to be associated with lower birth weight and shorter gestational age. OBJECTIVE: In a new Swedish cohort study on maternal asthma exposure and stress during pregnancy (MAESTRO), we have assessed if there is evidence of early fetal growth restriction in asthmatic women or if a growth restriction might come later during pregnancy. METHODS: We recruited women from eight antenatal clinics in Stockholm, Sweden. Questionnaires on background factors, asthma status and stress were assessed during pregnancy. The participants were asked to consent to collection of medical records including ultrasound measures during pregnancy, and linkage to national health registers. In women with and without asthma, we studied reduced or increased growth by comparing the second-trimester ultrasound with first-trimester estimation. We defined reduced growth as estimated days below the 10th percentile and increased growth as days above the 90th percentile. At birth, the weight and length of the newborn and the gestational age was compared between women with and without asthma. RESULTS: We enrolled 1693 participants in early pregnancy and collected data on deliveries and ultrasound scans in 1580 pregnancies, of which 18% of the mothers had asthma. No statistically significant reduced or increased growth between different measurement points were found when women with and without asthma were compared; adjusted odds ratios for reduced growth between first and second trimester 1.11 95% CI (0.63-1.95) and increased growth 1.09 95% CI (0.68-1.77). CONCLUSION AND CLINICAL RELEVANCE: In conclusion, we could not find evidence supporting an influence of maternal asthma on early fetal growth in the present cohort: Although the relatively small sample size, which may enhance the risk of a type II error, it is concluded that a potential difference is likely to be very small.

Osteoporosis and fracture risk associated with inhaled corticosteroid use among Swedish COPD patients: the ARCTIC study.

The effect of inhaled corticosteroids (ICS) on the risk of osteoporosis and fracture in patients with chronic obstructive pulmonary disease (COPD) remains uncertain. The aim of this study was to assess this risk in patients with COPD.Electronic medical record data linked to National Health Registries were collected from COPD patients and matched reference controls at 52 Swedish primary care centres from 2000 to 2014. The outcomes analysed were the effect of ICS on all fractures, fractures typically related to osteoporosis, recorded osteoporosis diagnosis, prescriptions of drugs for osteoporosis and a combined measure of any osteoporosis-related event. The COPD patients were stratified by the level of ICS exposure.A total of 9651 patients with COPD and 59 454 matched reference controls were analysed. During the follow-up, 19.9% of COPD patients had at least one osteoporosis-related event compared with 12.9% of reference controls (p<0.0001). Multivariate analysis in the COPD population demonstrated a dose-effect relationship, with high-dose ICS being significantly associated with any osteoporosis-related event (risk ratio 1.52 (95% CI 1.24-1.62)), while the corresponding estimate for low-dose ICS was 1.27 (95% CI 1.13-1.56) compared with COPD patients not using ICS. A similar dose-related adverse effect was found for all four of the specific osteoporosis-related events: all fractures, fractures typically related to osteoporosis, prescriptions of drugs for osteoporosis and diagnosis of osteoporosis.We conclude that patients with COPD have a greater risk of bone fractures and osteoporosis, and high-dose ICS use increased this risk further.

Inhaled corticosteroids and the risk of type 2 diabetes among Swedish COPD patients.

This study reports the association of ICS use and the risk of type 2 diabetes mellitus (T2DM) in Swedish patients with COPD using data from real-world, primary care settings. A total of 7078 patients with COPD were included in this analysis and the 5-year cumulative incidence rate per 100,000 person years was 1506.9. The yearly incidence rate per 100,000 person years ranged from 850 to 1919. Use of ICS especially at a high dose in patients with COPD was related to an increased risk of T2DM.

[The role of inhaled steroids in the treatment of COPD]. / Tillägg av inhalationssteroider vid KOL kan förebygga försämring.

The aim of COPD treatment is to reduce symptoms and prevent exacerbations. The pharmacological treatment is based on bronchodilator treatment which reduces symptoms and prevents exacerbations. If patients have exacerbations despite bronchodilator treatment it is important to consider adding inhaled corticosteroids (ICS). Concomitant asthma is always an indication for ICS treatment. Studies have shown that measurement of blood eosinophil count predicts the effect of adding ICS to bronchodilators. Higher b-eos (≥ 0,3 × 109/l) strengthens the indication for ICS. A large number of COPD patients in Sweden are treated with both bronchodilators and ICS without a history of exacerbations. It is important to assess that the indication is correct at follow up of these patients.

Clinical, Epidemiological and Experimental Approaches to Assess Adverse Health Outcomes of Indoor Biomass Smoke Exposure: Conclusions from An Indo-Swedish Workshop in Mysuru, January 2020.

This report summarizes the outcome of a workshop held in Mysuru, India in January 2020 addressing the adverse health effects of exposure to biomass smoke (BMS). The aim of the workshop was to identify uncertainties and gaps in knowledge and possible methods to address them in the Mysuru study on Determinants of Health in Rural Adults (MUDHRA) cohort. Specific aims were to discuss the possibility to improve and introduce new screening methods for exposure and effect, logistic limitations and other potential obstacles, and plausible strategies to overcome these in future studies. Field visits were included in the workshop prior to discussing these issues. The workshop concluded that multi-disciplinary approaches to perform: (a) indoor and personalized exposure assessment; (b) clinical and epidemiological field studies among children, adolescents, and adults; (c) controlled exposure experiments using physiologically relevant in vitro and in vivo models to understand molecular patho-mechanisms are warranted to dissect BMS-induced adverse health effects. It was perceived that assessment of dietary exposure (like phytochemical index) may serve as an important indicator for understanding potential protective mechanisms. Well trained field teams and close collaboration with the participating hospital were identified as the key requirements to successfully carry out the study objectives.

Bringing asthma care into the twenty-first century.

Despite access to diagnostic tests and effective therapies, asthma often remains misdiagnosed and/or poorly controlled or uncontrolled. In this review, we address the key issues of asthma diagnosis and management, recent evidence for levels of asthma control, the consequences of poor control and, in line with that, explore the potential reasons for poor asthma control and acute exacerbations. Based on recent evidence and current guidelines, we also aim to provide practical answers to the key questions of how to improve asthma management, with the best possible prevention of exacerbations, addressing the basics-adherence, inhaler misuse, obesity and smoking-and how to facilitate a new era of asthma care in the twenty-first century. We hope this review will be useful to busy primary care clinicians in their future interactions with their patients with both suspected and proven asthma.

Increased MUC1 plus a larger quantity and complex size for MUC5AC in the peripheral airway lumen of long-term tobacco smokers.

There is little information on mucins versus potential regulatory factors in the peripheral airway lumen of long-term smokers with (LTS+) and without (LTS-) chronic obstructive pulmonary disease (COPD). We explored these matters in bronchoalveolar lavage (BAL) samples from two study materials, both including LTS+ and LTS- with a very similar historic exposure to tobacco smoke, and healthy non-smokers (HNSs; n=4-20/group). Utilizing slot blot and immunodetection of processed (filtered and centrifuged), as well as unprocessed BAL samples from one of the materials, we compared the quantity and fraction of large complexes of mucins. All LTS displayed an enhanced (median) level of MUC5AC compared with HNS. LTS- displayed a higher level of large MUC5AC complexes than HNS while LTS+ displayed a similar trend. In all LTS, total MUC5AC correlated with blood leukocytes, BAL neutrophil elastase and net gelatinase activity. Large mucin complexes accounted for most MUC5B, without clear group differences. In all LTS, total MUC5B correlated with total MUC5AC and local bacteria. In the same groups, large MUC5B complexes correlated with serum cotinine. MUC1 was increased and correlated with BAL leukocytes in all LTS whereas MUC2 was very low and without clear group differences. Thus, the main part of MUC5AC and MUC5B is present as large complexes in the peripheral airway lumen and historic as well as current exposure to tobacco smoke emerge as potential regulatory factors, regardless of COPD per se. Bacteria, leukocytes and proteinases also constitute potential regulatory factors, of interest for future therapeutic strategies.