The Swedish National Airway Register (SNAR): development, design and utility to date.

BACKGROUND: The Swedish National Airway Register (SNAR) was initiated in 2013 to ensure and improve the quality of care for patients with asthma and COPD. AIM: To describe the development and design of SNAR, and to study the 2019 data to evaluate its potential utility related to improvement of quality of care. METHODS: SNAR includes data from patients with asthma (both children and adults) and COPD from primary, secondary and tertiary care, and also, for COPD inpatient care. Data on diagnostic investigations (e.g. spirometry, blood sample, skin prick test), symptom-scores, comorbidities and prescribed treatments are registered. The registrations are entered manually by healthcare professionals, or directly transferred from electronic medical records to a web-based platform. RESULTS: In 2019, 1000 clinics participated and data were directly transferred by about 88% of them. The register included data on 205,833 patients with asthma and 80,372 with COPD (of these, 5% had both diagnoses). Registrations of new patients and follow-up visits from primary and secondary/tertiary care in 2019 were completed for 75,707 patients with asthma (11,818 children <12 yr, 6545 adolescents 12-17 yr, and 57,344 adults >17 yr) and 38,117 with COPD. Depending on age and disease group, 43-77% had performed spirometry, 36-65% Asthma Control Test, and 60% COPD Assessment Test. The prevalence of current smoking was about 2% in adolescents, 10% in adults with asthma, and 34% in COPD. For these, smoking cessation support was offered to 27%, 38% and 51%, respectively. Overall, limited data were available on investigation of allergy, 6-min walk test, patient education and written treatment plans. Regarding asthma, sex-differences in disease management were evident. CONCLUSION: SNAR has cumulatively registered data from over 270,000 individuals, and the register is important for patients, caregivers, authorities, politicians and researchers to evaluate the effect of treatment and to ensure high and equal quality of care nationwide.

Budesonide inhaler device switch patterns in an asthma population in Swedish clinical practice (ASSURE).

BACKGROUND: Dry powder inhaler (DPI) device switch in asthma treatment could potentially increase with the entrance of new devices. We examined the switch patterns of budesonide (BUD) DPI analogues available in Sweden. METHODS: This observational real-life study linked primary healthcare medical records data from the Västra Götaland region to national Swedish registries, and included asthma patients (ICD-10-CM J45) prescribed BUD in a multidose DPI. Index date: first dispense of BUD DPI. Switch date: prescription of another BUD DPI device. Study outcomes (switch vs. non-switch) were exacerbations and prescription of short-acting ß2 -agonists. Study period was 1 July 2005 to 31 October 2013. RESULTS: Overall, 15,169 asthma patients were on treatment with BUD DPI; 1178 (7.35%) switched to another BUD DPI during the study. Pair-wise 1:1 matching of switchers vs. non-switchers resulted in two groups of 463 patients each (mean age 36 years, 55% female patients). A 25% higher exacerbation rate was seen postswitch (0.40 vs. 0.32; p = 0.047). Switchers were 4.5 year younger and had lower medication possession rate than non-switchers. Switch without primary healthcare visit did not differ between groups regarding consultations and exacerbations (no visit 4.96 and 0.90; visit 4.29 and 0.77, respectively). However, patients without primary healthcare visit at switch had significantly more outpatient hospital visits (2.01 vs. 0.81; p < 0.001). CONCLUSIONS: Considering the low switch rate, asthma patients and physicians in Swedish general practice seem reluctant to switch to another BUD DPI device. Switch, especially without primary healthcare visit, was associated with decreased asthma control resulting in higher exacerbation rate and more outpatient hospital visits.

Detection of mild emphysema by computed tomography density measurements.

PURPOSE: To assess the ability of a conventional density mask method to detect mild emphysema by high-resolution computed tomography (HRCT); to analyze factors influencing quantification of mild emphysema; and to validate a new algorithm for detection of mild emphysema. MATERIAL AND METHODS: Fifty-five healthy male smokers and 34 never-smokers, 61-62 years of age, were examined. Emphysema was evaluated visually, by the conventional density mask method, and by a new algorithm compensating for the effects of gravity and artifacts due to motion and the reconstruction algorithm. Effects of the reconstruction algorithm, slice thickness, and various threshold levels on the outcome of the density mask area were evaluated. RESULTS: Forty-nine percent of the smokers had mild emphysema. The density mask area was higher the thinner the slice irrespective of the reconstruction algorithm and threshold level. The sharp algorithm resulted in increased density mask area. The new reconstruction algorithm could discriminate between smokers with and those without mild emphysema, whereas the density mask method could not. The diagnostic ability of the new algorithm was dependent on lung level. At about 90% specificity, sensitivity was 65-100% in the apical levels, but low in the rest of the lung. CONCLUSION: The conventional density mask method is inadequate for detecting mild emphysema, while the new algorithm improves the diagnostic ability but is nevertheless still imperfect.

Bronchial mucosal mast cells in asymptomatic smokers relation to structure, lung function and emphysema.

The pathologic mechanisms of chronic obstructive pulmonary disease (COPD) most certainly involves neutrophil granulocytes, cytotoxic T-cells, macophages and mast cells. The aim of this study was to investigate the relation between the number of mast cells in different compartments in bronchial biopsies of central proximal airways to structural changes, lung function tests and emphysema detected by high resolution computed tomography (HRCT). Twenty nine asymptomatic smoking and 16 never-smoking men from a population study were recruited. Central bronchial biopsies were stained to identify mast cells by immunohistochemistry. The number of mast cells in the epithelium, lamina propria and smooth muscle as well as epithelial integrity and thickness of the tenascin and laminin layer were determined. Smokers had increased numbers of mast cells in all compartments (P<0.001). Structural changes were correlated to mast cell numbers with the closest associations to mast cell numbers in the smooth muscle [epithelial integrity (R(S)=-0.48, P=0.008), laminin layer (R(S)=0.63, P=0.0002), tenascin layer (R(S)=0.40, P=0.03)]. Similar correlations between mast cells and lung function tests were seen [functional residual capacity (FRC) (R(S)=0.60, P=0.0006), total lung capacity (TLC) (R(S)=0.44, P=0.02) and residual volume (RV) (R(S)=0.41, P=0.03)]. No correlations could be detected between mast cells and FEV1 or to emphysema. Smoking is associated with an increase of mast cells in all compartments of the bronchial mucosa, including smooth muscle, and this is related to altered airway structure and function.

High-resolution computed tomography in healthy smokers and never-smokers: a 6-year follow-up study of men born in 1933.

PURPOSE: To elucidate whether emphysematous lesions and other high-resolution computed tomography (HRCT) findings considered associated with smoking are part of a progressive process, and to measure the extent to which similar changes are found in never-smokers. MATERIAL AND METHODS: Healthy smokers and never-smokers were recruited from a randomized epidemiological study and investigated with a 6-year interval. Emphysema, parenchymal and subpleural nodules, ground-glass opacities, bronchial alterations, and septal lines were evaluated in 66 subjects (40 smokers, 11 of whom had stopped smoking in the interval, and 26 never-smokers). Lung function was tested. RESULTS: All except emphysematous lesions were present to some extent in never-smokers. Emphysema, parenchymal nodules, and septal lines occurred significantly more in current smokers, and a progression in extent of emphysema, ground-glass opacities, bronchial alterations and septal lines was seen. There was no significant change among those who stopped and never-smokers except for bronchial alterations, which progressed in never-smokers. CONCLUSION: In healthy, elderly never-smokers a low extent of various HRCT findings has to be considered normal. Emphysema, parenchymal nodules, and ground-glass opacities are indicative of smoking-induced disease. Further progress may cease if smoking is stopped.

Value of air trapping in detection of small airways disease in smokers.

PURPOSE: To test the hypothesis that diffuse and/or focal air trapping are sensitive indicators of airflow obstruction in smoker's small airways disease, when age, gender and presence of emphysematous lesions were allowed for. MATERIAL AND METHODS: Fifty-eight smokers and 34 never smokers, recruited from a randomized population study of men born in 1933, were investigated by HRCT and by extended pulmonary function tests, including a sensitive test for small airways disease (N2 slope). Diffuse air trapping was evaluated by calculating a quotient of mean lung density at expiration and inspiration. Focal air trapping was scored visually by consensus. RESULTS: Diffuse air trapping did not differ between non-emphysematous smokers and never smokers. Furthermore, diffuse air trapping correlated well to the quotient between the residual volume and total lung capacity (RV/TLC, p = 0.01) and was consequently higher in emphysematous smokers than in never smokers. Focal air trapping was found as frequently in smokers without emphysema as in never smokers. Smokers with emphysema showed significantly less focal air trapping. Neither the N2 slope nor any of the other lung function variables differed between those with and without focal air trapping among non-emphysematous smokers. CONCLUSION: Neither diffuse nor focal air trapping are sensitive indicators of smoker's small airways disease.

Relationship between inflammatory cells and structural changes in the lungs of asymptomatic and never smokers: a biopsy study.

BACKGROUND: A study was undertaken to investigate the relationship between inflammatory cells and structural changes in the mucosa of the airways in an epidemiological sample of a group of asymptomatic smokers (smokers who had never sought medical attention for respiratory problems) and in non-smoking subjects. METHODS: Bronchial biopsy specimens were taken from 29 smokers and 16 never smokers and stained with monoclonal antibodies HNL, EPO, AA1, CD68 in order to identify neutrophils, eosinophils, mast cells, and macrophages, respectively. The biopsy specimens were also stained with monoclonal antibodies to the cytokines interleukin (IL)-1beta and IL-8. Structural changes were identified by staining the biopsy specimens with antibodies to tenascin and laminin and by evaluating the condition of the epithelial layer. RESULTS: The numbers of all inflammatory cells and of cytokine staining cells were significantly increased in smokers. The thickness of the tenascin and laminin layers was increased in the smoking group and the integrity of the epithelial layer was significantly reduced. In smokers the epithelial integrity was negatively correlated with the number of eosinophils and macrophages. The thickness of the tenascin and laminin layers was positively correlated with AA1 and EPO positive cells only. CONCLUSION: High numbers of inflammatory cells are present in the bronchial mucosa of asymptomatic smokers which have a clear relationship with the impaired epithelial integrity. The increased thickness of the laminin and tenascin layers in these subjects was strongly related to the presence of eosinophils and mast cells, suggesting a role for these cells in tissue remodelling of the airways of smokers.

Neutrophil-associated activation markers in healthy smokers relates to a fall in DL(CO) and to emphysematous changes on high resolution CT.

Smoking is a risk factor for developing chronic obstructive pulmonary disease (COPD), but there are no good indicators for early identification of subjects who will develop symptomatic COPD. The aim of this study was to investigate inflammatory mechanisms related to changes in lung function and emphysematous changes on high resolution computed tomography (HRCT) in 'healthy' smokers. Subjects were 60-year-old men from a population study. Bronchoscopy was performed in 30 smokers and 18 who had never smoked. Blood tests, lung function measurements and HRCT were carried out in 58 and 34 subjects, respectively. In comparison with never-smokers, smokers had higher levels of myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein (ECP) and lysozyme in blood, higher levels of MPO, interleukin-8 (IL-8) and HNL in bronchial lavage (BL), and of IL-8, HNL and interleukin-lbeta (IL-1beta) in bronchoalveolar lavage (BAL). Smokers also had lower levels of Clara cell protein 16 (CC-16) in blood. HNL in BL and BAL showed strong correlations to other inflammatory markers (MPO, IL-8, IL-1beta). The variations in MPO in BL were explained by variations in HNL (R2 =0.69), while these variations in BAL were explained by variations in HNL and IL-1beta (R2 = 0.76). DL(CO) was the lung function variable most closely related to MPO and IL-8 in BL and BAL and to IL-1beta in BAL. In a multiple regression analysis, MPO, IL-1beta, IL-8 and CC-16 in BL and MPO in BAL contributed to the explanation of variations in DL(CO) to 41% and 22%. respectively, independent of smoking habits. In smokers with emphysematous lesions on HRCT, HNL in BAL correlated to emphysema score (r(s) = 0.71). We conclude that 'healthy' smoking men with a near normal FEV1 show signs of inflammation in the lower airways that are related to a decrease in DL(CO) and to emphysematous lesions on HRCT. This inflammation seems to be the result of both monocyte/macrophage and neutrophil activation.

Respiratory symptoms relate to physiological changes and inflammatory markers reflecting central but not peripheral airways. A study in 60-year-old 'healthy' smokers and never-smokers.

The aim of this study was to evaluate the relationship between respiratory symptoms, lung function and inflammatory markers in 'healthy' smokers. The study population was recruited from an epidemiological study with subjects of the same age, 60 years. Only smokers who considered themselves healthy (n=58) and a random sample of never-smokers (n=34) were investigated. All subjects underwent lung function tests--spirometry, carbon monoxide transfer (DLco) and the single-breath N2 method (N2 test)--together with high-resolution computed tomography (HRCT). A flexible bronchoscopy with a bronchoalveolar lavage (BAL) was performed in 30 smokers and 18 never-smokers. Bronchial biopsies were also taken. Smokers who reported non-specific respiratory problems, chronic bronchitis and wheezing in a symptom questionnaire had a lower forced expiratory volume in 1 sec (FEV1), FEV% and specific airway conductance (sGaw), lung function tests supposed to reflect the more central airways, than smokers without respiratory symptoms. A limited number of smokers with occasional non-specific respiratory problems also had more cytotoxic T cells (CD8) in bronchial biopsies. No differences were found in DLCO and the N2 test, lung function tests supposed to reflect the more peripheral airways including the alveoli, HRCT-diagnosed emphysema or inflammatory markers in blood and BAL between smokers with and without respiratory symptoms. It is concluded that even when smokers consider themselves 'healthy' they have mild symptoms that are related more to physiological changes and inflammatory markers that may reflect events in the central airways than to changes that may reflect events in the peripheral airways.

The expression of lymphocyte surface antigens in bronchial biopsies, bronchoalveolar lavage cells and blood cells in healthy smoking and never-smoking men, 60 years old.

In this study we investigated if smoking subjects with a normal or slightly decreased lung function differ in the lymphocyte pattern compared to never-smokers. In a group of 'healthy' smokers (n = 58) and never-smokers (n = 34) 60 years old, we investigated the lymphocyte pattern in both BAL (n = 30 and n = 18 respectively), bronchial epithelium and lamina propria (n = 14 and n = 10 respectively) and blood. We found that all subjects, despite smoking history, had a higher number of CD8+ cells per mm2 in the epithelium compared to the lamina propria in the bronchial biopsies. In smokers, these CD8+ cells were significantly negatively correlated to FEV1 (r = -0.56, P = 0.04). In smokers, the number of CD8+ lymphocytes was higher and the T cell activation markers (CD57+ and CD28+) were lower in BAL, than in never-smokers. This last finding was also seen in blood for CD3+ 57+. We conclude, that in 'healthy' smokers the lymphocyte patterns are different compared to never-smokers, to some extent in BAL. There is also a relation between lymphocytes in the bronchial mucosa and lung function. This has previously been shown in patients with chronic obstructive pulmonary disease (COPD) and chronic bronchitis but not in asymptomatic smokers.

Emphysematous lesions and lung function in healthy smokers 60 years of age.

We aimed to study the occurrence of emphysematous lesions in symptom free smoking men of about 60 years of age and in a matching group of never-smoking men and the relationship between pulmonary changes at high resolution computed tomography (HRCT) and lung function tests. Our investigation included 57 smoking and 32 never-smoking healthy men from a randomized epidemiological study. HRCT was performed at full inspiration with a 1.5 mm slice thickness and a 3 cm inter-slice distance. Evaluation was made by two radiologists unaware of smoking history. Emphysematous lesions were scored visually. Pulmonary function tests were performed including spirometry and diffusion capacity test (DLCO). Emphysematous changes were demonstrated in 25 of 57 smokers but in only one never-smoker. DLCO/VA was the most sensitive test for early emphysematous lesions. It also correlated with radiographical scoring. Emphysematous lesions were evident in 44% of the healthy symptom free smokers. HRCT may reveal early emphysematous lesions in smokers before clinical symptoms have developed.

A comparison of the expression of lymphocyte activation markers in blood, bronchial biopsies and bronchoalveolar lavage: evidence for an enrichment of activated T lymphocytes in the bronchoalveolar space.

In this study healthy never-smoking subjects (n = 18) were recruited from a population study. Bronchoalveolar lavage (BAL), blood lymphocytes and bronchial biopsies, analysed both in the epithelium and lamina propria, were stained for T and B lymphocytes, natural killer (NK) cells and different subpopulations of T lymphocytes. In BAL, significantly higher proportions of T lymphocytes (CD3), T lymphocyte activation markers; HLA-DR, CD26+, CD49a+, CD54+ and CD69+, helper T (CD3+4+) and memory helper T lymphocytes (CD4+45RO+29+) and memory T lymphocytes (CD3+45RO+) were found, compared to blood. However, the proportion of IL-2 receptor-positive T lymphocytes (CD25+) was lower in BAL than in blood. A previously described higher ratio of CD3+4+/CD3+8+ in BAL than in blood (3.4 vs 1.7; P = 0.001) was confirmed. In bronchial biopsies, we found significantly higher numbers of CD8+ cell profiles per mm2 in the epithelial compared to the lamina propria compartment. We conclude that healthy never-smoking men have higher levels of activated memory T lymphocytes in BAL than in blood, and that the T-cell subpopulations differ in the epithelial compared to the lamina propria compartment in the bronchial mucosa and these compartments should be analysed separately. It is reasonable to think that there is a gradient from blood to the airway lumen where T cells are recruited from blood to take part in the defense towards damaging agents.

N-isobutyrylcysteine, a donor of systemic thiols, does not reduce the exacerbation rate in chronic bronchitis.

N-isobutyrylcysteine (NIC), a new thiol compound that is not rapidly hydrolysed to give higher levels of free thiols in the body than N-acetylcysteine (NAC), was used to test if the effect of NAC on exacerbations in chronic bronchitis was an effect of the unhydrolysed thiol compound. Smokers or exsmokers with chronic bronchitis forced expiratory volume in one second (FEV1) >40% and reversibility < or = 10% predicted were treated with oral NIC 300 mg b.i.d. or placebo for 24 weeks. Steroids, NAC, antibiotics, and nonsteroid anti-inflammatory drugs use were restricted. Exacerbations were recorded by a respiratory symptom diary card and the time to onset of the first exacerbation after the start of treatment was measured using life-table analysis. Spirometry was performed at each visit. Six hundred and thirty-seven patients were randomized to treatment with NIC (n=316) or placebo (n=321). NIC did not prolong the time to first exacerbation (life-table analysis, p=0.59) and no increase in FEV1 or forced vital capacity was observed. Altered taste perception, taste loss and anosmia occurred more often in the NIC group (p<0.001). In conclusion, N-isobutyrylcysteine, a N-acetylcysteine-like drug with a greater bioavailability has, contrary to N-acetylcysteine, no effect on exacerbations in chronic bronchitis. This suggests that the effect of N-acetylcysteine on exacerbations in chronic bronchitis is not due to the relatively low free thiol levels (other than glutathione) produced by N-acetylcysteine therapy.