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.

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.

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.

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.

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.

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.

Organic dust, causing both oxidative stress and Nrf2 activation, is phagocytized by bronchial epithelial cells.

Inhalation of organic dust (OD) from swine confinement facilities leads to pulmonary inflammation, airway hyperresponsiveness, and oxidative stress. In mice, pretreatment with a hydroxyl radical scavenger prevents airway inflammation and airway hyperresponsiveness (AHR) induced by OD exposure. We sought to determine a mechanism by which OD could induce oxidative stress in bronchial epithelial cells. Human bronchial epithelial cells (BEAS-2B or NHBE) were treated with various concentrations of OD, followed by evaluation of intracellular oxidative stress using 2',7'-dichlorofluorescein diacetate (DCFDA). After stimulation with OD, gene expression of antioxidant genes was assessed by real-time quantitative PCR followed by quantification of Nrf2 nuclear translocation using a luciferase reporter assay. Phagocytic markers (CD36 and CD68) were analyzed by FACS. Cells were treated with an actin inhibitor, cytochalasin D, before OD exposure and evaluated for Nrf2 nuclear translocation and DCFDA. Mice were pretreated with sulforaphane, the Nrf2 activator, before OD exposure and evaluated for pulmonary inflammation and airway reactivity. OD induced a time- and concentration-dependent increase in DCFDA. mRNA expression levels of Nrf2-dependent genes and Nrf2 nuclear translocation were increased after OD exposure. OD exposure increased the expression of CD68 and CD36. Cytochalasin D prevented oxidative stress and Nrf2 nuclear translocation after OD. Pretreatment with sulforaphane prevented OD-induced inflammation and AHR while increasing the uptake of OD in bronchial epithelial cells. Bronchial epithelial cells can phagocytose OD, resulting in an increase in endogenous oxidative stress. Nrf2-dependent mechanisms mediate the antioxidant response to OD.

Prevalence, characteristics and management of frequently exacerbating asthma patients: an observational study in Sweden (PACEHR).

The aim of the study was to investigate the prevalence, management and characteristics of asthma patients with frequent exacerbations.Data from asthma patients (aged ≥18 years) identified in primary care medical records were linked to Swedish national health registries. Exacerbations were defined as hospitalisations, emergency visits and/or collection of oral steroids. Frequent exacerbations were defined as two or more exacerbations per year during the 3-year observation period.Of 18 724 asthma patients, 81.49% had no exacerbations and 6.3% had frequent exacerbations in the year prior to the index date. Frequent exacerbations were observed yearly for 1.8% of the patients. Frequent exacerbators were older, more often females, and had increased eosinophil and neutrophil counts, lower lung function, and more comorbidities than patients without exacerbations. There was a slight increase in asthma medication claims and a slight decrease in physician visits compared with baseline, both in the group with and the group without frequent exacerbations.Patients with frequent exacerbations were characterised by greater age, female predominance, high eosinophil and neutrophil counts, and high prevalence of comorbidities. This study indicates that the Swedish healthcare system lacks efficiency to adjust treatment and management for this patient group. With new treatment options targeting severe asthma available, identification of these patients should be in focus to ensure reduction of exacerbations.

Prevalence and management of severe asthma in primary care: an observational cohort study in Sweden (PACEHR).

BACKGROUND: Severe and uncontrolled asthma is associated with increased risk of exacerbations and death. A substantial proportion of asthma patients have poor asthma control, and a concurrent COPD diagnosis often increases disease burden. The objective of the study was to describe the prevalence and managemant of severe asthma in a Swedish asthma popuöation. METHODS: In this observational cohort study, primary care medical records data (2006-2013) from 36 primary health care centers were linked to data from national mandatory Swedish health registries. The studied population (>18 years) had a record of drug collection for obstructive pulmonary disease (ATC code R03) during 2011-2012, and a physician diagnosed asthma (ICD-10 code J45-J46) prior to drug collection. Severe asthma was classified as collection of high dose inhaled steroid (> 800 budesonide or equivalent per day) and leukotriene receptor antagonist and/or long-acting beta-agonist. Poor asthma control was defined as either collection of ≥600 doses of short-acting beta-agonists, and/or ≥1 exacerbation(s) during the year post index date. RESULTS: A total of 18,724 asthma patients (mean 49 years, 62.8% women) were included, of whom 17,934 (95.8%) had mild to moderate and 790 (4.2%) had severe asthma. Exacerbations were more prevalent in severe asthma (2.59 [2.41-2.79], Relative Risk [95% confidence interval]; p < 0.001). Poor asthma control was observed for 28.2% of the patients with mild to moderate asthma and for more than half (53.6%) of the patients with severe asthma (<0.001). Prior to index, one in five severe asthma patients had had a contact with secondary care and one third with primary care. A concurrent COPD diagnosis increased disease burden. CONCLUSION: Severe asthma was found in 4.2% of asthma patients in Sweden, more than half of them had poor asthma control, and most patients had no regular health care contacts.

Health care resource utilization and cost for asthma patients regularly treated with oral corticosteroids - a Swedish observational cohort study (PACEHR).

BACKGROUND: Patients with severe uncontrolled asthma may receive oral corticosteroid (OCS) treatment regularly. The present study investigated the health care resource utilization and cost in regularly OCS treated Swedish asthma patients. METHODS: Primary care medical records data were linked to data from Swedish national health registries. Patients ≥18 years with a drug claim for obstructive pulmonary diseases during 2007-2009 (index date) and a prior asthma diagnosis, were classified by their OCS claims during the 12-months' post index period: regular OCS equals ≥5 mg per day; periodic OCS less than 5 mg per day; or non-OCS users. Cost of asthma- and OCS-morbidity-related health care resource utilization were calculated. RESULTS: A total of 15,437 asthma patients (mean age 47.8, female 62.6%), whereof 223 (1.44%) were regular OCS users, 3054 (19.7%) were periodic, and 12,160 (78.7%) were non-OCS users. Regular OCS users were older and more often females, had lower lung function, greater eosinophil count and more co-morbidities at baseline compared with the other groups. Age-adjusted annual total health care cost was three-times greater in the regular OCS group (€5615) compared with the non-OCS users (€1980) and twice as high as in the periodic OCS group (€2948). The major cost driver in the non-OCS and periodic OCS groups were primary care consultations, whereas inpatient costs were the major cost driver in the regular OCS group. The asthma related costs represented 10-12% of the total cost in all three groups. CONCLUSION: In this real-life asthma study in Sweden, the total yearly cost of health care resource utilization for a regular OCS user was three times greater than for a patient with no OCS use, indicating substantial economic and health care burden for asthma patients on regular oral steroid treatment.

Identifying the associated risks of pneumonia in COPD patients: ARCTIC an observational study.

BACKGROUND: Inhaled corticosteroids (ICS) are associated with an increased risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD). Other factors such as severity of airflow limitation and concurrent asthma may further raise the possibility of developing pneumonia. This study assessed the risk of pneumonia associated with ICS in patients with COPD. METHODS: Electronic Medical Record data linked to National Health Registries were collected from COPD patients and matched reference controls in 52 Swedish primary care centers (2000-2014). Levels of ICS treatment (high, low, no ICS) and associated comorbidities were assessed. Patients were categorized by airflow limitation severity. RESULTS: A total of 6623 patients with COPD and 48,566 controls were analyzed. Patients with COPD had a more than 4-fold increase in pneumonia versus reference controls (hazard ratio [HR] 4.76, 95% confidence interval [CI]: 4.48-5.06). ICS use increased the risk of pneumonia by 20-30% in patients with COPD with forced expiratory volume in 1 s ≥ 50% versus patients not using ICS. Asthma was an independent risk factor for pneumonia in the COPD population. Multivariate analysis identified independent predictors of pneumonia in the overall population. The highest risk of pneumonia was associated with high dose ICS (HR 1.41, 95% CI: 1.23-1.62). CONCLUSIONS: Patients with COPD have a greater risk of pneumonia versus reference controls; ICS use and concurrent asthma increased the risk of pneumonia further.

Effects of tiotropium bromide on airway hyperresponsiveness and inflammation in mice exposed to organic dust.

INTRODUCTION: Acute exposure to organic dust (OD) in pig barns induces intense airway inflammation with neutrophilia and hyperresponsiveness. This reaction is likely associated with increased cholinergic activity. Therefore, the involvement of cholinergic mechanisms in the reaction to acute exposure of OD was investigated in mice using the long-acting muscarinic antagonist tiotropium. METHODS: BALB/c mice received tiotropium (2-200 ng) intranasally on day 1 of the study. On days 2-4, mice received vehicle or OD (25 µg) intranasally. Airway hyperresponsiveness to methacholine was assessed 24 h following the last OD exposure. Bronchoalveolar lavage (BAL) fluid, lung tissue and blood were collected for analyses. RESULTS: Organic dust elevated airway responsiveness to methacholine compared with controls (PBS) assessed as Newtonian resistance (1.5 ±â€¯0.1 vs 0.9 ±â€¯0.1 cm H2O x s/mL), tissue damping (12.4 ±â€¯1.4 vs 8.9 ±â€¯0.9 cm H2O∙s/mL) and tissue elastance (41.1 ±â€¯5.3 vs 27.2 ±â€¯2.5 cm H2O∙s/mL). Tiotropium (200 ng) decreased the Newtonian resistance and tissue damping after exposure to PBS or OD. Organic dust exposure increased inflammatory cells in BAL fluid by almost 400%, mainly due to neutrophil influx, which was unaffected by tiotropium. Organic dust increased levels of mainly Th1 mediators. Tiotropium treatment attenuated OD-induced release of IL-2, IL-4 and IL-6. CONCLUSIONS: Tiotropium decreased the OD-induced increase of specific cytokines without influencing the OD-induced increase of airway responsiveness and neutrophil infiltration into the lungs. We conclude that the cholinergic pathway contributes to the pro-inflammatory effects caused by inhalation of OD from pig barns.

Neutrophilic oxidative stress mediates organic dust-induced pulmonary inflammation and airway hyperresponsiveness.

Airway exposure to organic dust (OD) from swine confinement facilities induces airway inflammation dominated by neutrophils and airway hyperresponsiveness (AHR). One important neutrophilic innate defense mechanism is the induction of oxidative stress. Therefore, we hypothesized that neutrophils exacerbate airway dysfunction following OD exposure by increasing oxidant burden. BALB/C mice were given intranasal challenges with OD or PBS (1/day for 3 days). Mice were untreated or treated with a neutrophil-depleting antibody, anti-Ly6G, or the antioxidant dimethylthiourea (DMTU) prior to OD exposure. Twenty-four hours after the final exposure, we measured airway responsiveness in response to methacholine (MCh) and collected bronchoalveolar lavage fluid to assess pulmonary inflammation and total antioxidant capacity. Lung tissue was harvested to examine the effect of OD-induced antioxidant gene expression and the effect of anti-Ly6G or DMTU. OD exposure induced a dose-dependent increase of airway responsiveness, a neutrophilic pulmonary inflammation, and secretion of keratinocyte cytokine. Depletion of neutrophils reduced OD-induced AHR. DMTU prevented pulmonary inflammation involving macrophages and neutrophils. Neutrophil depletion and DMTU were highly effective in preventing OD-induced AHR affecting large, conducting airways and tissue elastance. OD induced an increase in total antioxidant capacity and mRNA levels of NRF-2-dependent antioxidant genes, effects that are prevented by administration of DMTU and neutrophil depletion. We conclude that an increase in oxidative stress and neutrophilia is critical in the induction of OD-induced AHR. Prevention of oxidative stress diminishes neutrophil influx and AHR, suggesting that mechanisms driving OD-induced AHR may be dependent on neutrophil-mediated oxidant pathways.

Linoleic acid-derived lipid mediators increase in a female-dominated subphenotype of COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality; however, the role of inflammatory mediators in its pathobiology remains unclear. The aim of this study was to investigate the influence of gender in COPD on lipid mediator levels.Bronchoalveolar lavage fluid (BALF) and serum were obtained from healthy never-smokers, smokers and COPD patients (Global Initiative for Chronic Obstructive Lung Disease stage I-II/A-B) (n=114). 94 lipid mediators derived from the cytochrome-P450, lipoxygenase, and cyclooxygenase pathways were analysed by liquid chromatography-mass spectrometry.Multivariate modelling identified a 9-lipid panel in BALF that classified female smokers with COPD from healthy female smokers (p=6×10(-6)). No differences were observed for the corresponding male population (p=1.0). These findings were replicated in an independent cohort with 92% accuracy (p=0.005). The strongest drivers were the cytochrome P450-derived epoxide products of linoleic acid (leukotoxins) and their corresponding soluble epoxide hydrolase (sEH)-derived products (leukotoxin-diols). These species correlated with lung function (r=0.87; p=0.0009) and mRNA levels of enzymes putatively involved in their biosynthesis (r=0.96; p=0.003). Leukotoxin levels correlated with goblet cell abundance (r=0.72; p=0.028).These findings suggest a mechanism by which goblet cell-associated cytochrome-P450 and sEH activity produce elevated leukotoxin-diol levels, which play a putative role in the clinical manifestations of COPD in a female-dominated disease sub-phenotype.

Evaluation of the use of Swedish integrated electronic health records and register health care data as support clinical trials in severe asthma: the PACEHR study.

BACKGROUND: In the development of new drugs for severe asthma, it is a challenge from an ethical point of view to randomize severe asthma patients to placebo, and to obtain long-term safety data due to discontinuations. The aim of this study was to evaluate the feasibility of using electronic health record (EHR) data to create a real-world reference population of uncontrolled asthmatic patients to supplement the concurrent control/placebo group in long-term studies of asthma. METHODS: EHR data from 36 primary care centres and a University hospital in Sweden were linked to Swedish mandatory health registers (2005-2013), creating a population covering 33 890 asthma patients, including data on co-morbidities, risk factors and laboratory/respiratory measurements. A severe asthma EHR reference cohort was established. We used logistic regression to estimate the propensity score (probability) of each RCT or EHR patient existing in the EHR cohort given their covariates. RESULTS: We created an EHR-derived reference cohort of 240 patients, matching the placebo group (N = 151) in an RCT of severe asthma. The exacerbation rate during follow-up in the EHR study population was 1.24 (weighted) compared to 0.9 in the RCT placebo group. Patients in the EHR cohort were of similar age as in the RCT placebo group, 50.6 years versus 50.1 years; had slightly higher body mass index 27.0 kg/m2 versus 27.3 kg/m2; and consisted of 40% versus 34% males. CONCLUSIONS: The results indicate that EHRs provide an opportunity to supplement the control group in RCTs of severe diseases.

Comparing human respiratory adverse effects after acute exposure to particulate matter in conventional and particle-reduced swine building environments.

OBJECTIVES: To evaluate innate immunity responses, lung function and symptoms in volunteers acutely exposed to organic dust in swine buildings after installing particle separators aimed to reduce particulate matter exposure. METHODS: 11 healthy participants were exposed in 2 different facilities, with and without installed particle separators, in a cross-over design including 2-3 weeks wash-out between the 2 exposures. Size, distribution and composition of particulate matter and endotoxins in the air were measured. Lung function (spirometry), bronchial responsiveness, symptoms questionnaire and markers of innate immunity in blood and nasal lavage were measured before and after the 3-hour exposures. RESULTS: The number of particles, in particular fine particles sized 0.3-0.5 µm, was reduced in the particle-separated swine building environment (PSE) compared with that in the conventional building (CE). In the PSE, headache (p=0.03) and increased body temperature (p=0.016) were less pronounced than in the CE. The expression of toll-like receptors (TLR)2 and TLR4 on blood monocytes significantly increased (p=0.016 and 0.017, respectively) while cluster of differentiation (CD)14 on neutrophils decreased (p=0.05) after exposure in the CE, yet with no difference between the 2 exposures. Compared with the conventional environment, exposure to the PSE yielded lower interleukin (IL)-6 (p=0.02) and IL-8 (p=0.04) levels in the upper respiratory tract, as assessed by nasal lavage. CONCLUSIONS: Particulate matter and organic dust in the swine building were reduced after installing particle separators, which, in naïve never exposed volunteers, in turn reduced adverse health effects caused by acute exposure in swine buildings compared with exposure to the conventional swine building environment.

Evaluation of the global lung function initiative 2012 reference values for spirometry in a Swedish population sample.

BACKGROUND: The Global Lung Function Initiative 2012 (GLI) reference values are currently endorsed by several respiratory societies but evaluations of applicability for adults resident in European countries are lacking. The aim of this study was to evaluate if the GLI reference values are appropriate for an adult Caucasian Swedish population. METHODS: During 2008-2013, clinical examinations including spirometry were performed on general population samples in northern Sweden, in which 501 healthy Caucasian non-smokers were identified. Predicted GLI reference values and Z-scores were calculated for each healthy non-smoking subject and the distributions and mean values for FEV1, FVC and the FEV1/FVC ratio were examined. The prevalence of airway obstruction among these healthy non-smokers was calculated based on the Lower Limit of normal (LLN) criterion (lower fifth percentile) for the FEV1/FVC ratio. Thus, by definition, a prevalence of 5% was expected. RESULTS: The Z-scores for FEV1, FVC and FEV1/FVC were reasonably, although not perfectly, normally distributed, but not centred on zero. Both predicted FEV1 and, in particular, FVC were lower compared to the observed values in the sample. The deviations were greater among women compared to men. The prevalence of airway obstruction based on the LLN criterion for the FEV1/FVC ratio was 9.4% among women and 2.7% among men. CONCLUSIONS: The use of the GLI reference values may produce biased prevalence estimates of airway obstruction in Sweden, especially among women. These results demonstrate the importance of validating the GLI reference values in different countries.

Combination of budesonide/formoterol on demand improves asthma control by reducing exercise-induced bronchoconstriction.

BACKGROUND: In mild asthma exercise-induced bronchoconstriction (EIB) is usually treated with inhaled short-acting ß2 agonists (SABAs) on demand. OBJECTIVE: The hypothesis was that a combination of budesonide and formoterol on demand diminishes EIB equally to regular inhalation of budesonide and is more effective than terbutaline inhaled on demand. METHODS: Sixty-six patients with asthma (>12 years of age) with verified EIB were randomised to terbutaline (0.5 mg) on demand, regular budesonide (400 µg) and terbutaline (0.5 mg) on demand, or a combination of budesonide (200 µg) + formoterol (6 µg) on demand in a 6-week, double-blind, parallel-group study (ClinicalTrials.gov identifier: NCT00989833). The patients were instructed to perform three to four working sessions per week. The main outcome was EIB 24 h after the last dosing of study medication. RESULTS: After 6 weeks of treatment with regular budesonide or budesonide+formoterol on demand the maximum post-exercise forced expiratory volume in 1 s fall, 24 h after the last medication, was 6.6% (mean; 95% CI -10.3 to -3.0) and 5.4% (-8.9 to -1.8) smaller, respectively. This effect was superior to inhalation of terbutaline on demand (+1.5%; -2.1 to +5.1). The total budesonide dose was approximately 2.5 times lower in the budesonide+formoterol group than in the regular budesonide group. The need for extra medication was similar in the three groups. CONCLUSIONS: The combination of budesonide and formoterol on demand improves asthma control by reducing EIB in the same order of magnitude as regular budesonide treatment despite a substantially lower total steroid dose. Both these treatments were superior to terbutaline on demand, which did not alter the bronchial response to exercise. The results question the recommendation of prescribing SABAs as the only treatment for EIB in mild asthma.

Compartment differences of inflammatory activity in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with local and systemic inflammation. The knowledge of interaction and co-variation of the inflammatory responses in different compartments is meagre. METHOD: Healthy controls (n = 23), smokers with (n = 28) and without (n = 29) COPD performed spirometry and dental examinations. Saliva, induced sputum, bronchoalveolar lavage (BAL) fluid and serum were collected. Inflammatory markers were assessed in all compartments using ELISA, flow cytometry and RT-PCR. RESULTS: Negative correlations between lung function and saliva IL-8 and matrix metalloproteinase-9 (MMP-9) were found in smokers with COPD. IL-8 and MMP-9 in saliva correlated positively with periodontal disease as assessed by gingival bleeding in non-smokers.Tumor necrosis factor-α (TNF-α) in saliva, serum and TNF-α mRNA expression on macrophages in BAL-fluid were lower in smokers than in non-smokers. There were positive correlations between soluble TNF-α receptor 1 (sTNFR1) and soluble TNF-α receptor 2 (sTNFR2) in sputum, BAL-fluid and serum in all groups. Sputum interleukin-8 (IL-8) or interleukin-6 (IL-6) was positively correlated with sTNFR1 or sTNFR2 in non-smokers and with sTNFR2 in COPD. CONCLUSION: Saliva which is convenient to collect and analyse, may be suitable for biomarker assessment of disease activity in COPD. An attenuated TNF-α expression was demonstrated by both protein and mRNA analyses in different compartments suggesting that TNF-α response is altered in moderate and severe COPD. Shedding of TNFR1 or TNFR2 is similarly regulated irrespective of airflow limitation.