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The pulmonary mechanics of anesthetized rabbits were studied during induced acute bronchoconstriction. The bronchoconstricting agent was acetyl-β-methylcholine which, when injected intravenously as in these experiments, appeared to act via the pulmonary circulation. In spontaneously breathing animals functional residual capacity increased with bronchospasm, and dynamic compliance decreased. This decrease correlated in magnitude with the severity of the bronchoconstriction. Frequency changed in random direction. Dynamic compliance recovered more slowly than conductance after bronchoconstriction unless the lungs were inflated just prior to each recovery measurement, in which case the two variables recovered equally quickly. This observation suggested that airway occlusion accounted for part of the decrease in dynamic compliance. Bronchoconstriction reduced semistatic compliance in paralyzed artificially ventilated animals and also static compliance, which was measured by arresting breathing with phrenic stimulation, in spontaneously breathing animals. These observations supported the above hypothesis. Submitted on September 26, 1962

Sandford AJ, Malhotra D, Boezen HM, Siedlinski M, Postma DS, Wong V, Akhabir L, He JQ, Connett JE, Anthonisen NR, Pare PD, Biswal S. NFE2L2 pathway polymorphisms and lung function decline in chronic obstructive pulmonary disease. Physiol Genomics 44: 754-763, 2012. First published June 12, 2012; doi:10.1152/physiolgenomics.00027.2012.-An oxidant-antioxidant imbalance in the lung contributes to the development of chronic obstructive pulmonary disease (COPD) that is caused by a complex interaction of genetic and environmental risk factors. Nuclear erythroid 2-related factor 2 (NFE2L2 or NRF2) is a critical molecule in the lung's defense mechanism against oxidants. We investigated whether polymorphisms in the NFE2L2 pathway affected the rate of decline of lung function in smokers from the Lung Health Study (LHS)(n = 547) and in a replication set, the Vlagtwedde-Vlaardingen cohort (n = 533). We selected polymorphisms in NFE2L2 in genes that positively or negatively regulate NFE2L2 transcriptional activity and in genes that are regulated by NFE2L2. Polymorphisms in 11 genes were significantly associated with rate of lung function decline in the LHS. One of these polymorphisms, rs11085735 in the KEAP1 gene, was previously shown to be associated with the level of lung function in the Vlagtwedde-Vlaardingen cohort but not with decline of lung function. Of the 23 associated polymorphisms in the LHS, only rs634534 in the FOSL1 gene showed a significant association in the Vlagtwedde-Vlaardingen cohort with rate of lung function decline, but the direction of the association was not consistent with that in the LHS. In summary, despite finding several nominally significant polymorphisms in the LHS, none of these associations were replicated in the Vlagtwedde-Vlaardingen cohort, indicating lack of effect of polymorphisms in the NFE2L2 pathway on the rate of decline of lung function.

Two primary chitinases have been identified in humans--acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host's immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV(1)) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV(1) and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV(1). Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.

Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases.We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval.A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P0.001). The scores on the St. George's Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04).Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).

Aims Surfactant protein-D (SP-D) is a lung-specific protein that is detectable in human plasma. We determined the relationship of circulating SP-D to cardiovascular disease (CVD) and total mortality in subjects with and without CVD. Methods and results Plasma SP-D levels were measured in 806 patients who underwent coronary angiography to assess its predictive value for cardiovascular mortality. Serum SP-D levels were also measured in a replication cohort to assess its relationship with CVD events in 4468 ex- and current smokers without a known history of coronary artery disease (CAD). Patients who died during follow-up had significantly higher plasma SP-D levels than those who survived (median 85.4 vs. 64.8 ng/mL; P < 0.0001). Those in the highest quintile of SP-D had 4.4-fold higher risk of CVD mortality than those in the lowest quintile ( P < 0.0001) independent of age, sex, and plasma lipid levels. In a group of current and ex-smokers without a known history of CAD, serum SP-D levels were elevated in those who died or were hospitalized for CVD compared with those who did not (median 99.8 vs. 90.6 ng/mL; P = 0.0001). Conclusion Circulating SP-D is a good predictor of cardiovascular morbidity and mortality and adds prognostic information to well-established risk factors such as age, sex, and plasma lipids and is a promising biomarker to link lung inflammation/injury to CVD.

BACKGROUND: Currently, no reference or normative values for spirometry based on a randomly selected Canadian population exist.OBJECTIVE: The aim of the present analysis was to construct spirometric reference values for Canadian adults 20 to 90 years of age by combining data collected from healthy lifelong nonsmokers in two population-based studies.METHOD: Both studies similarly used random population sampling, conducted using validated epidemiological protocols in the Canadian Obstructive Lung Disease study, and the Lung Health Canadian Environment study. Spirometric lung function data were available from 3042 subjects in the COLD study, which was completed in 2009, and from 2571 subjects in the LHCE study completed in 1995. A total of 844 subjects 40 to 90 years of age, and 812 subjects 20 to 44 years of age, were identified as healthy, asymptomatic, lifelong nonsmokers, and provided normative reference values for spirometry. Multiple regression models were constructed separately for Caucasian men and women for the following spirometric parameters: forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio, with covariates of height, sex and age. Comparison with published regression equations showed that the best agreement was obtained from data derived from random populations.RESULTS: The best-fitting regression models for healthy, never-smoking, asymptomatic European-Canadian men and women 20 to 90 years of age were constructed. When age- and height-corrected FEV1, FVC and FEV1/FVC ratio were compared with other spirometry reference studies, mean values were similar, with the closest being derived from population-based studies.CONCLUSION: These spirometry reference equations, derived from randomly selected population-based cohorts with stringently monitored lung function measurements, provide data currently lacking in Canada.

To cite this article: Chan-Yeung M, Anthonisen NR, Becklake MR, Bowie D, Sonia Buist A, Dimich-Ward H, Ernst P, Sears MR, Siersted HC, Sweet L, Van Til L, Manfreda J. Geographical variations in the prevalence of atopic sensitization in six study sites across Canada. Allergy 2010; 65: 1404–1413. Abstract Background: Geographical variations in atopic sensitization in Canada have not been described previously. This study used the standardized protocol of the European Community Respiratory Health Survey-1 (ECRHS-1) to investigate the distribution and predictors of atopic sensitization in six sites across Canada and to compare the results with some ECRHS-1 centers. Methods: Adults aged 20–44 years in six study sites across Canada underwent allergy skin testing using 14 allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae) cat, cockroach, grasses (Timothy grass, Kentucky grass), molds (Cladosporium herbarium, Alternaria alternata, Aspergillus fumigatus, Penicillium), trees (tree mix, birch, Olea europea), and common ragweed. Results: The overall prevalence of atopy (skin test over 0 mm to any allergen) was 62.7%. There was significant geographical variation in the prevalence of atopy in the six study sites (lowest 55.6% [95% C.I.51.3–59.9] in Prince Edward Island, highest 66.0 [61.7–70.3] in Montreal) and of sensitization to each of the allergens tested even after adjustment for confounders. When the first eight of the nine allergens in the ECRHS were used to estimate the prevalence of atopic sensitization, the prevalence of atopy in Canada was 57% compared with 35.2% overall for centers in the ECRHS. The prevalence of atopy in Vancouver (57% [52.3–61.8]) was close to that of Portland, Oregon (52.1% [46.2–58.0]). Conclusion: There was a significant variation in atopic sensitization among different study sites across Canada. The prevalence of atopic sensitization is relatively high in Canada compared with sites in the ECRHS and this may, in part, account for the high prevalence of asthma and asthma symptoms in Canada.

Debate exists about the immunogenicity and protective efficacy of antibodies produced by the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in chronic obstructive pulmonary disease (COPD). The 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) induces a more robust immune response than PPSV23 in healthy elderly adults.We hypothesized that serotype-specific IgG antibody concentration and functional antibody activity would be superior after PCV7 vaccination compared with PPSV23 in moderate to severe COPD. We also posited that older age and prior PPSV23 vaccination would be associated with reduced vaccine responsiveness.One hundred twenty patients with COPD were randomized to PPSV23 (63 subjects) or PCV7 (57 subjects). IgG concentrations were determined by ELISA; functional antibody activity was assayed with a standardized opsonophagocytosis assay and reported as an opsonization killing index (OPK). Increases in serotype-specific IgG and OPK at 1 month post vaccination were compared within and between vaccine groups.Both vaccines were well tolerated. Within each study group, postvaccination IgG and OPK were higher than baseline (P0.01) for all serotypes. Adjusted for baseline levels, postvaccination IgG was higher in the PCV7 group than the PPSV23 group for all seven serotypes, reaching statistical significance for five (P0.05). PCV7 resulted in a higher OPK for six of seven serotypes (statistically greater for four) compared with PPSV23. In multivariate analyses, younger age, vaccine naivety, and receipt of PCV7 were associated with increased OPK responses.PCV7 induces a superior immune response at 1 month post vaccination compared with PPSV23 in COPD. Older age and prior PPSV23 reduce vaccine responsiveness. Clinical trial registered with www.clinicaltrials.gov (NCT00457977).

Background: Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which probably plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is a functional single nucleotide polymorphism (SNP), -174G/C, in the promoter region of IL6 . It was hypothesised that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers. Methods: Seven and five SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in 1 s (FEV1) over 5 years and baseline FEV1 at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of nine IL6 SNPs was genotyped in 389 cases of COPD from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS). Results: In the LHS, three IL6 SNPs were associated with decline in FEV1 (0.023⩽p⩽0.041 in additive models). Among them, the IL6 \_-174C allele was associated with a rapid decline in lung function. The association was more significant in a genotype-based analysis (p = 0.006). In the NETT-NAS study, IL6 \_-174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6 _-174G/C, were associated with susceptibility to COPD (0.01⩽p⩽0.04 in additive genetic models). Conclusion: The results suggest that the IL6 _-174G/C SNP is associated with a rapid decline in FEV1 and susceptibility to COPD in smokers.

Granulocyte-macrophage colony-stimulating factor (CSF), also known as CSF2, and granulocyte CSF, also known as CSF3, are important survival and proliferation factors for neutrophils and macrophages. The objective of the present study was to determine whether single nucleotide polymorphisms (SNPs) of CSF2 and CSF3 are associated with lung function in smoking-induced chronic obstructive pulmonary disease. In total, five SNPs of CSF2 and CSF3 were studied in 587 non-Hispanic white subjects with the fastest (n = 281) or the slowest (n = 306) decline of lung function selected from among continuous smokers in the National Heart, Lung, and Blood Institute Lung Health Study (LHS). These SNPs were also studied in 1,074 non-Hispanic white subjects with the lowest (n = 536) or the highest (n = 538) baseline lung function at the beginning of the LHS. An increase in the number of CSF3 -1719T alleles was significantly associated with protection against low lung function (odds ratio 0.73, 95% confidence interval 0.56-0.95), and was still significant after adjustment for multiple comparisons. There was also a significant association of a CSF3 haplotype with baseline levels of forced expiratory volume in one second. No association was found for CSF2 SNPs and lung function, nor was there evidence of epistasis. In conclusion, genetic variation in colony-stimulating factor 3 is associated with cross-sectionally measured lung function in smokers.

Christine Macie, Kate Wooldrage, Jure Manfreda, Nicholas AnthonisenDepartment of Medicine, University of Manitoba, Winnipeg, Manitoba, CanadaAbstract: We used the Manitoba Health database to examine the relationship between use of inhaled respiratory drugs in people with chronic obstructive respiratory diseases and cardiovascular hospitalizations from 1996 through 2000. The drugs examined were beta agonists [BA], ipratropium bromide IB, and inhaled steroids (ICS). End points were first hospitalizations for supraventricular tachycardia, myocardial infarction, heart failure or stroke. A nested case control analysis was employed comparing people with and without cardiovascular events. Cases and controls were matched for gender and age, and conditional logistic regression was used in multivariate analysis considering other respiratory drugs, respiratory diagnosis and visit frequency, non-respiratory, non-cardiac comorbidities, and receipt of drugs for cardiovascular disease. In univariate analyses, BA, IB and ICS were all associated with hospitalizations for cardiovascular disease, but in multivariate analyses ICS did not increase risk while both BA and IB did. There were interactions between respiratory and cardiac drugs receipt in that bronchodilator associated risks were higher in people not taking cardiac drugs; this was especially true for stroke. There were strong interactions with specific cardiac drugs; for example, both BA and IB substantially increased the risk of supraventricular tachycardia in patients not anti-arryhthmic agents, but not in the presence of such agents. We conclude that bronchodilator therapy for chronic obstructive diseases is associated with increased cardiovascular risk, especially in patients without previous cardiovascular diagnoses, and that this is unlikely due to the severity of the respiratory disease, since risk was not increased with ICS.Keywords: bronchodilator therapy, inhaled corticosteroids, nested case control study

Interleukin (IL)-10 is a type-2 T-helper cell cytokine with a broad spectrum of anti-inflammatory actions. Inflammation plays an important role in the pathogenesis of chronic obstructive pulmonary disease. It was hypothesised that single nucleotide polymorphisms (SNPs) of the genes encoding IL-10 ( IL10 ) and the α subunit of its receptor ( IL10RA ) are associated with changes in, or value of, forced expiratory volume in one second (FEV 1 ) in smoking-induced chronic obstructive pulmonary disease. In total, eleven SNPs of IL10 and IL10RA were studied in 586 White subjects, selected from continuous smokers followed for 5 yrs in the Lung Health Study, who showed the fastest (n = 280) and slowest (n = 306) decline in FEV 1 . These 11 SNPs were also studied in 1,072 participants exhibiting the lowest (n = 538) and highest (n = 534) baseline FEV 1 at the beginning of the Lung Health Study. No association was found in the primary analyses. Although a subgroup analysis showed that the IL-10 3368A allele was associated with a fast decline in FEV 1 , the association did not pass correction for multiple comparisons. No gene–gene interaction of IL10 with IL10RA was found. There was no association of polymorphisms of the genes encoding interleukin-10 and the α subunit of its receptor with the rate of decline in, or value of, forced expiratory volume in one second in smoking-induced chronic obstructive pulmonary disease.

Asthma treatment guidelines recommend addition of controller medications for patients with poorly controlled asthma. We compared the effectiveness of once-daily oral controller therapy with either an antileukotriene receptor antagonist (montelukast) or low-dose theophylline added to existing medications in patients with poorly controlled asthma.We conducted a randomized, double-masked, placebo-controlled trial in 489 participants with poorly controlled asthma randomly assigned to placebo, theophylline (300 mg/d), or montelukast (10 mg/d). Participants were monitored for 24 wk to measure the rate of episodes of poor asthma control (EPACs) defined by decreased peak flow, increased beta-agonist use, increased oral corticosteroid use, or unscheduled health care visits.There was no significant difference in EPAC rates (events/person/yr) compared with placebo: low-dose theophylline, 4.9 (95% confidence interval [CI], 3.6-6.7; not significant); montelukast, 4.0 (95% CI, 3.0-5.4; not significant); and placebo, 4.9 (95% CI, 3.8-6.4). Both montelukast and theophylline caused small improvements in prebronchodilator FEV(1) of borderline significance. Nausea was more common with theophylline only during the first 4 wk of treatment. Neither treatment improved asthma symptoms or quality of life. However, in patients not receiving inhaled corticosteroids, addition of low-dose theophylline significantly (p0.002) improved asthma control and symptoms as well as lung function.Neither montelukast nor low-dose theophylline lowered the EPAC rate of poor asthma control in patients with poorly controlled asthma despite improved lung function. For patients not using inhaled corticosteroids, low-dose theophylline improved asthma symptom control more than montelukast or placebo, and provides a safe and low-cost alternative asthma treatment.

Importance Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited. Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control. Objective To determine whether a soy isoflavone supplement improves asthma control in adolescent and adult patients with poorly controlled disease. Design, Setting, and Participants Multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2010 and August 2012 at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network. Three hundred eighty-six adults and children aged 12 years or older with symptomatic asthma while taking a controller medicine and low dietary soy intake were randomized, and 345 (89%) completed spirometry at week 24. Interventions Participants were randomly assigned to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks. Main Outcomes and Measures The primary outcome measure was change in forced expiratory volume in the first second (FEV 1 ) at 24 weeks. Secondary outcome measures were symptoms, episodes of poor asthma control, Asthma Control Test score (range, 5-25; higher scores indicate better control), and systemic and airway biomarkers of inflammation. Results Mean changes in prebronchodilator FEV 1 over 24 weeks were 0.03 L (95% CI, −0.01 to 0.08 L) in the placebo group and 0.01 L (95% CI, −0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different ( P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% CI, 1.42-2.54] vs soy isoflavones, 2.20 [95% CI, 1.53-2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% CI, 2.7-4.1] vs soy isoflavones, 3.0 [95% CI, 2.4-3.7]), and changes in exhaled nitric oxide (placebo, −3.48 ppb [95% CI, −5.99 to −0.97 ppb] vs soy isoflavones, 1.39 ppb [95% CI, −1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL ( P Conclusions and Relevance Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma. Trial Registration clinicaltrials.gov Identifier:NCT01052116

Genetic variants in the tumour necrosis factor (TNF) gene have been investigated in chronic obstructive pulmonary disease (COPD). However, there are many instances of nonreplication of these associations due to insufficient power or other factors. In this study, a large number of subjects were examined to elucidate whether genetic variations of TNF and/or lymphotoxin A (LTA), which is clustered with TNF, are associated with variations in lung function among smokers. The present authors designed two nested case-control studies in the National Heart, Lung, and Blood Institute Lung Health Study (LHS), which enrolled 5,887 smokers. The first design included continuous smokers who had the fastest (n = 279) and the slowest (n = 304) decline of lung function during the 5-yr follow-up period, and the second included the subjects who had the lowest (n = 533) and the highest (n = 532) post-bronchodilator % predicted forced expiratory volume in one second at the start of the LHS. Within the TNF and LTA region, 10 tagging single-nucleotide polymorphisms were selected and genotyped. Unlike the previous associations between TNF-308 and COPD in Asians, the current study found no association between either of the two phenotypes and the LTA and TNF polymorphisms. In conclusion, these results support the findings of previous studies in late-onset chronic obstructive pulmonary disease in Caucasian populations.

Study objectives To assess the influence of inhaled corticosteroids (ICSs) on mortality in COPD patients, which is currently a controversial topic. Setting Manitoba Health maintains a population-wide research database that includes pharmaceutical information. Design and patients We examined mortality in people 90 to 365 days after hospital discharge for COPD, comparing those persons who received inhaled steroids within 90 days of hospital discharge with those who did not. Cox proportional hazards models were used with adjustments for other respiratory drugs, comorbidities, and physician visits before and after hospital discharge. We also compared mortality in patients who received inhaled steroids with those who received other respiratory drugs, but not inhaled steroids, and those who received neither. Using nested case control analysis, we examined the time of receipt of inhaled steroids in relation to fatal events. Results In people > 65 years of age, inhaled steroids were associated with a 25% reduction in mortality between 90 and 365 days after hospital discharge, while mortality increased with bronchodilator use, physician visits, age, and comorbidities. The exclusion of people who had also received a diagnosis of asthma or had received inhaled steroids before hospitalization did not change the result. Inhaled steroids were associated with an even larger mortality reduction in people aged 35 to 64 years. People who received bronchodilators but no steroids had higher mortality than people who received no bronchodilators or received both bronchodilators and inhaled steroids. The reduction in all-cause mortality was largely due to the decreased number of cardiovascular deaths. The receipt of inhaled steroids within 30 days of death was protective, but this was not the case for greater time intervals. Conclusions Therapy with ICSs reduced mortality in COPD patients; the effect was particularly notable for cardiovascular death and was short term in that it was dependent on recent exposure.

Background A worldwide increase has been noted in the prevalence of asthma, but the data for other allergic disorders are less consistent. Objective To study 14-year trends in utilization of physician resources for asthma and compare them to trends for allergic rhinitis. Methods We studied visits to physicians by Manitoba residents for asthma ( International Classification of Diseases, Ninth Revision, Clinical Modification [ ICD-9-CM ] code 493) and allergic rhinitis ( ICD-9 code 477) between 1985 and 1998. Prevalence and incidence of physician resources utilization were calculated annually for the total population and by age groups. Aggregate statistics and frequency of physician resources utilization were also analyzed. Results The prevalence and incidence of physician resources utilization for asthma increased more than for allergic rhinitis; differences were most striking in the youngest age groups. In adults, the differences were smaller and changed little with time. Most of the increase in asthma care occurred in children and in people without allergic rhinitis. Overall, 17% of Manitobans were diagnosed as having asthma, and the average asthmatic patient made 6 visits. Approximately 14% had an allergic rhinitis diagnosis, each person being seen twice on average. Coexistence of asthma and allergic rhinitis led to increased physician resources utilization for each of the conditions. Conclusions Trends in utilization of physician resources for allergic rhinitis differed strikingly from trends for asthma, particularly in the youngest age group. Asthma and allergic rhinitis affected comparable proportions of the population, but a diagnosis of asthma resulted in much higher utilization of physician resources. The relationship of physician-diagnosed asthma and atopy, as indicated by the diagnosis of allergic rhinitis, appears to have weakened with time in children but not in adults.

Summary Background : Although variation in the human leukocyte antigen ( HLA ) locus is associated with various diseases, there have been a limited number of studies that have examined the possible role of HLA in chronic obstructive pulmonary disease (COPD). Only HLA-B7 has been shown to be correlated with low forced expiratory volume in 1s (FEV 1 ) in Caucasians; however, this finding has not been replicated. The aim of this study was to investigate the contribution of the HLA-B7 allele to COPD and to rate of decline of lung function. Methods : We determined the prevalence of HLA-B7 in a group of COPD patients and a non-obstructed control group of smokers by using a polymerase chain reaction-based genotyping assay. We also determined the prevalence of HLA-B7 in smokers selected from the National Heart Lung and Blood Institute, Lung Health Study for having the fastest and slowest decline of lung function. Results : No significant difference was found in the frequency of HLA-B7 between the COPD and non-obstructed groups. There was also no significant association of HLA-B7 with rate of decline of lung function. Conclusion : These data indicate that HLA-B7 does not contribute to COPD or rate of decline of FEV 1 in smokers.

BACKGROUND: Previous data indicated that spirometry was underused in people with obstructive disease, especially those with chronic obstructive pulmonary disease (COPD).OBJECTIVE: To examine the use of respiratory drugs in patients with COPD and asthma, and to relate drug use to spirometry.METHODS: Manitoba Health maintains a database of physician services remunerated by fees that includes spirometry. The database contains the diagnosis and patient identifiers, as well as sex, date of birth and residential postal code. Similar identifiers are used in the provincial pharmacare program that records prescriptions dispensed at retail pharmacies. These databases were examined for the time period between 1996 to 2000, and people over 35 years of age diagnosed with asthma, COPD or both were identified. The frequency of spirometry in these patients and their use of respiratory drugs was determined.RESULTS: Spirometry and drug prescription frequencies increased with the number of physician visits (including those for bronchitis), but their patterns differed. Patients with asthma or asthma plus COPD had considerably higher rates of drug prescription and slightly higher spirometry rates than did those with COPD. Patients with asthma and asthma plus COPD who underwent spirometry were slightly more likely to receive drugs than those who did not undergo spirometry; this trend was more striking in patients with COPD. However, approximately 30% of patients with COPD who had five physician visits and who underwent spirometry did not receive drugs; this was true for approximately 10% of similar patients with asthma. Patients with asthma generally received beta-agonists and inhaled steroids; these agents were less commonly given to patients with COPD, who instead were given anticholinergics much more often than were asthmatics. Patients who were diagnosed with asthma plus COPD had beta-agonist and inhaled corticosteroid prescription rates similar to asthmatics, and anticholinergic prescription rates similar to patients with COPD. Theophylline and antileukotriene drugs were used less often than were inhaled agents. In patients with asthma, drugs were frequently discontinued, and during drug use, prescription refills were consistent with an intake of 30.9% of the prescribed doses. In patients with COPD, discontinuing drugs early was uncommon, and refills were consistent with the use of 54% of the prescribed amounts. The same was true of patients with both COPD and asthma.DISCUSSION: Drug prescription was considerably more common in patients labelled with asthma or COPD plus asthma than in patients with COPD. Spirometry was also less common in patients with COPD but had a distinct influence on the frequency of drug prescription. Patterns of drug prescription were predictable, and patterns of drug use indicated poor compliance, in agreement with other data. The results suggest that COPD symptoms may be discounted and patients systematically undertreated or the diagnosis could frequently be applied to people with trivial disease or both.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a common occurrence and characterize the natural history of the disease. Over the past decade, new knowledge has substantially enhanced our understanding of the pathogenesis, outcome and natural history of AECOPD. The exacerbations not only greatly reduce the quality of life of these patients, but also result in hospitalization, respiratory failure, and death. The exacerbations are the major cost drivers in consumption of healthcare resources by COPD patients. Although bacterial infections are the most common etiologic agents, the role of viruses in COPD exacerbations is being increasingly recognized. The efficacy of antimicrobial therapy in acute exacerbations has established a causative role for bacterial infections. Recent molecular typing of sputum isolates further supports the role of bacteria in AECOPD. Isolation of a new strain of Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae was associated with a considerable risk of an exacerbation. Lower airway bacterial colonization in stable patients with COPD instigates airway inflammation, which leads to a protracted self-perpetuating vicious circle of progressive lung damage and disease progression. A significant proportion of patients treated for COPD exacerbation demonstrate incomplete recovery, and frequent exacerbations contribute to decline in lung function. The predictors of poor outcome include advanced age, significant impairment of lung function, poor performance status, comorbid conditions and history of previous frequent exacerbations requiring antibacterials or systemic corticosteroids. These high-risk patients, who are likely to harbor organisms resistant to commonly used antimicrobials, should be identified and treated with antimicrobials with a low potential for failure. An aggressive management approach in complicated exacerbations may reduce costs by reducing healthcare utilization and hospitalization.

Objective: The objective of this cohort study was to determine if complications of pregnancy and labor, characteristics at birth, and exposure to infections influence the incidence of asthma in the first 6 years of life. Design: We identified all children born between 1980 and 1990 in the Province of Manitoba, Canada. We used records of physician contacts (inpatient and outpatient) and services of the universal provincial health insurance plan to follow up 170,960 children from birth to the age of 6 years to identify the first diagnosis of asthma. Information on mothers and siblings was also obtained to determine family history of disease and exposure to infections. Results: During the study period, a diagnosis of asthma was made in 14.1% of children by the age of 6 years. The incidence was higher in boys than in girls, in those with family history of allergic diseases. It was higher in urban than in rural areas, and lowest in those born in winter. Asthma was more likely in those with low birth weight and premature birth. Certain congenital abnormalities and complications of pregnancy and labor also increased the risk of asthma. The risk of asthma increased with maternal age. Both upper and lower respiratory infections increased the risk of subsequent asthma, and this effect was more important than exposure to familial respiratory infections, which also tended to increase asthma risk. The risk of asthma decreased with the number of siblings when siblings had a history of allergic disorders. Conclusions: In addition to genetic influences, intrauterine and labor conditions are determinants of asthma. Exposure to both upper and lower respiratory tract infections increases the risk; these infections do not explain the protective effect associated with the increasing number of siblings.

Objectives Geographic variability in reported prevalences of asthma worldwide could in part relate to interpretation of symptoms and diagnostic biases. Bronchial responsiveness measurements provide objective evidence of a common physiologic characteristic of asthma. We measured bronchial responsiveness using the standardized protocol of the European Community Respiratory Health Survey (ECRHS) in six sites in Canada, and compared prevalences across Canada with international sites. Design Samples of 3,000 to 4,000 adults aged 20 to 44 years were randomly selected in Vancouver, Winnipeg, Hamilton, Montreal, Halifax, and Prince Edward Island, and a mail questionnaire was completed by 18,616 individuals (86.5%). Preselected random subsamples (n = 2,962) attended a research laboratory for examination including more detailed questionnaires, lung function testing including methacholine challenge, and skin testing with 14 allergens. Results Prevalences of bronchial hyperresponsiveness, measured as cumulative dose of methacholine required to produce a 20% fall from the post-saline solution FEV 1 ≤ 1 mg, ranged from 4.9% (95% confidence interval [CI], 1.6 to 8.5) in Halifax to 22.0% (95% CI, 18.1 to 26.0) in Hamilton (median, 10.7%). In all Canadian sites, bronchial hyperresponsiveness was more prevalent in women than in men. Neither the geographic nor gender differences were accounted for by differences in age, smoking, skin test reactivity, or baseline FEV 1. Geographic- and gender-related variability changed little when only bronchial hyperresponsiveness associated with asthma-like symptoms was considered. Conclusions A wide variability in bronchial responsiveness can occur within one country, almost as wide as the range found across all international sites participating in the ECRHS study and not explained by differences in gender, smoking, skin test reactivity, and FEV 1 . While gender variability in the prevalence of bronchial responsiveness is likely due to hormonal and immunologic factors, geographic variability is likely to result from environmental factors.

Targeted expression of interleukin (IL)-13 in the adult murine lung has been shown to cause emphysema. We hypothesized that variants in the IL13, IL13RA1, and IL4RA genes would be associated with an accelerated rate of decline of lung function among smokers. We determined the allele frequencies of five polymorphisms in the IL13, IL13RA1, and IL4RA genes in 588 continuing smokers chosen from the NHLBI Lung Health Study for having the fastest (n = 282) and slowest (n = 306) 5-yr rate of decline of lung function (mean change in FEV(1) %predicted/yr = -4.1 and +1.1, respectively). The IL4RA 551RR genotype was associated with rapid decline of lung function (odds ratio, 2.24; P = 0.043). However, none of the other four polymorphisms was associated with rate of decline in lung function. The association of 551RR with rapid decline of lung function became more significant in subjects who also had either the IL13 130RR or -1112TT genotypes. However, because multiple comparisons were made and only a few individuals had the 551RR genotype, these associations may represent type 1 error. Haplotypes consisting of alleles from the IL13 polymorphisms or from the IL4RA polymorphisms were not associated with rate of decline in lung function in smokers.

Background. Research on the long-term persistence of effects of interventions aimed at smoking cessation is limited. This paper examined the quitting behavior of individuals who were randomized to a smoking cessation intervention (SI) or to usual care (UC), at a point approximately 11 years later. Methods. The initial sample consisted of 5,887 adult smokers in 10 clinics who had evidence of airways obstruction. Two-thirds of the original participants were offered an intensive 12-week smoking cessation intervention. Of these, 4,517 were enrolled in the long-term follow-up study. Results. Randomized group assignment was a strong predictor of smoking behavior after 11 years, in that 21.9% of SI participants and only 6.0% of UC participants maintained abstinence throughout the interval. Logistic regressions identified covariates associated with abstinence. A higher proportion of abstinence was observed in participants that had been assigned to SI (OR = 4.45), were older (OR = 1.11, increment 5 years), had more years of education (OR = 1.05), and fewer cigarettes/day at baseline (OR = 0.90, increment 10 cigarettes). Conclusions. Smokers exposed to an aggressive smoking intervention program and who sustain abstinence for a five-year period are very likely to still be abstinent after 11 years.

Oxidative stress is believed to play an important role in the pathogenesis of smoking-induced chronic obstructive pulmonary disease. We hypothesized that polymorphisms of antioxidant genes glutathione S-transferase M1 (GSTM1), GSTT1, GSTP1, and heme oxygenase-1 (HMOX1) would be associated with susceptibility to accelerated decline of lung function in smokers. We genotyped 621 subjects (299 rapid decliners [change in forced expiratory volume in 1 second (DeltaFEV(1)) = -152 +/- 2.5 ml/year] and 322 nondecliners [DeltaFEV(1) = +15 +/- 1.5 ml/year]) selected from among smokers followed for 5 years in the National Heart, Lung, and Blood Institute Lung Health Study. Because genotype frequencies were different between ethnic groups, we limited the association study to 594 whites (286 rapid decliners and 308 nondecliners). None of the genotypes studied had a statistically significant effect on decline of lung function when analyzed separately. There was an association between rapid decline of lung function and presence of all three GST polymorphisms (odds ratio [OR] = 2.83; p = 0.03). A combination of a family history of chronic obstructive pulmonary disease with GSTP1 105Ile/Ile genotype was also associated with rapid decline of lung function (OR = 2.20; p = 0.01). However, due to the multiple comparisons that were made, these associations may represent type 1 error. There was no association between HMOX1 (GT)n alleles and the rate of decline in lung function in smokers.

The matrix metalloproteinases (MMPs) comprise a family of at least 20 proteolytic enzymes that play an essential role in tissue remodeling. MMP1 (interstitial collagenase), MMP9 (gelatinase B) and MMP12 (macrophage elastase) are thought to be important in the development of emphysema. A number of naturally occurring polymorphisms of human MMP gene promoters have been identified and found to alter transcriptional activity. Additionally, we detected a novel polymorphism in the MMP12 coding region (Asn357Ser). The aim of this study was to investigate the role of MMP polymorphisms in the development of chronic obstructive lung disease. We determined the prevalence of these polymorphisms in 590 continuing smokers chosen from the National Heart Lung and Blood Institute, Lung Health Study for having the fastest (n = 284) and slowest (n = 306) 5 year rate of decline of lung function. Of the five polymorphisms, only G-1607GG was associated with a rate of decline in lung function. The -1607GG allele was associated with a fast rate of decline (P = 0.02) [corrected]. However, haplotypes consisting of alleles from the MMP1 G-1607GG and MMP12 Asn357Ser polymorphisms were associated with rate of decline of lung function (P = 0.0007). These data suggest that polymorphisms in the MMP1 and MMP12 genes, but not MMP9, are either causative factors in smoking-related lung injury or are in linkage disequilibrium with causative polymorphisms.

BACKGROUND:Standard methods for population studies of asthma include surveying population samples using questionnaires and examining people in laboratories. These procedures are extremely expensive. It would be helpful if, at least for some purposes, they could be replaced by cheaper techniques with adequate validity. OBJECTIVES: To determine agreement between survey and database in regard to the prevalence of asthma.METHODS: Responses to survey questions about asthma symptoms in the past 12 months were linked to physician claims in the Manitoba Population Health Repository.RESULTS: The overall agreement was moderate (κ=0.45 to 0.50) and increased if two years of physician claims were studied (κ=0.55 to 0.59); studying additional years had no further effect on agreement. Sex and smoking did not significantly affect the kappa scores.CONCLUSIONS: There were several plausible reasons for discrepancies. Symptoms recorded on the survey were intrinsically different from those recorded for physician visits. Physicians also used other respiratory codes instead of asthma, and survey participants did not see a physician every year for asthma. The estimates of prevalence derived from the survey and the administrative database included two overlapping groups of people. In each, the diagnosis of asthma seems justifiable, although the agreement between the two groups was only moderate to substantial. Both methods are useful, although they are useful for different purposes. Health care utilization estimates may be particularly useful for studying trends over time.

This issue of the Canadian Respiratory Journal contains an interesting paper by Gauvreau et al (pages 26 to 32) concerning inhaled steroids and allergic bronchoprovocation in patients with asthma. They looked at data from previous studies that showed that steroids attenuate both early and late airway responses to allergens, and that this was associated with a reduction in sputum eosinophilia. The new finding is that the presence of neutrophils in the sputum blunted the increase in sputum eosinophils seen with allergen challenge. Gauvreau et al postulated that neutrophils and, presumably, neutrophilic inflammation may reduce the response to steroids in asthma. This is a little tricky, because the level of sputum neutrophils did not influence the degree of bronchoconstriction produced by allergen inhalation. Nevertheless, it seems reasonable to suppose that neutrophilic inflammation is less sensitive to steroids than that due, in large part, to eosinophils, and the hypothesis gives me the opportunity to consider the effects of inhaled steroids in chronic obstructive pulmonary disease (COPD), a disease characterized by neutrophilic inflammation. The effects of steroids in COPD have been controversial

BACKGROUND: Spirometry, the measurement of forced expiratory volume in 1 s and forced vital capacity, is recommended in the diagnosis and management of the obstructive lung diseases asthma and chronic obstructive pulmonary disease (COPD). The present report describes spirometry use in Manitoba and tests the hypothesis that regional spirometry use correlates with the prevalence of physician-diagnosed obstructive lung diseases.METHODS: Spirometry is remunerated on a fee-for-service basis by Manitoba Health. Like other physician services, billing data include a diagnosis, patient identifiers, as well as the patient’s sex, date of birth and residential postal code. Physician billings for spirometry for 1991 to 1998 were analyzed, comparing data with billings for physician visits for obstructive diseases. Four age groups were examined, as were income quintiles in Winnipeg, Manitoba. In addition, the prevalence of physician-diagnosed obstructive diseases were compared with spirometry rates in 49 service use areas of the province.RESULTS: Annually, about 3% of the Manitoba population underwent spirometry, and in aggregate, about 14% underwent spirometry during the eight years of the study. Rates in Winnipeg were higher than in the remainder of the province. Spirometry rates did not increase with time, and people who underwent spirometry had 1.4 to 1.7 tests/year. In children, higher income quintiles were tested more than lower income quintiles, while in adults, income quintiles were tested with equal frequency. People with obstructive lung disease accounted for about 75% of those tested, and in people with these diagnoses, the likelihood of testing increased approximately linearly with the number of physician visits for asthma or COPD. Children with asthma were tested less often than adults, and adults with asthma or both asthma and COPD were tested more often than those with COPD alone. In adults with asthma or asthma and COPD who had more than 10 physician visits for these diagnoses, testing rates were more than 70%, and multiple tests were common. In patients labelled with COPD only and with more than 20 physician visits, about one-third did not undergo spirometry. In children aged five to 14 years and in adults 15 to 44 years old, regional spirometry rates correlated well with regional asthma rates. Regional spirometry rates also correlated significantly with regional rates of asthma and/or COPD in people older than 34 years old.INTERPRETATION: Spirometry use is considerably higher in patients with asthma than in patients with COPD, suggesting that guidelines are followed more closely in patients with asthma, and that many patients are labelled with COPD without appropriate documentation. Spirometry use is apparently indicative of physician interest in the problem of obstructive lung diseases.

University of Manitoba, Winnipeg, Manitoba Correspondence: Dr NR Anthonisen, Respiratory Hospital, 810 Sherbrook Street, Room RS 319, Winnipeg, Manitoba R3A 1R8. Telephone 204-787-2562, fax 204-787-1220, e-mail nanthonisen@exchange.hsc.mb.ca Fifty years ago, chronic obstructive pulmonary disease (COPD) was the ideal disease for physiologically oriented clinicians to study, for a number of reasons. First, it was becoming recognized as a major health problem. Second, it could only be diagnosed reliably by physiological testing; x-rays did not work. Third, it was associated with a lot of interesting pathophysiology, including cor pulmonale, alterations in the control of ventilation, and perhaps most interesting of all, abnormalities that were primarily related to the distributions of ventilation and/or perfusion as opposed to global inadequacy of either of them. Thus, the study of COPD was part and parcel of the work of pioneers in Canadian respiratory medicine as indicated by Peter Macklem in the initial chapter of the present issue (pages 383-392). The emphasis was largely on pathophysiology and lung function. Thus, Christie (1) described the mechanical properties of the lung – reduced recoil and increased resistance – in emphysema before coming to Canada, as did Cherniack (2) somewhat later. Bates (3) developed a method for measuring diffusing capacity and showed that it was frequently reduced in emphysema, and infrequently reduced in asthma, an observation that has stood the test of time (4). Bates was the key author of three editions of Respiratory Function in Disease (3,5,6), an enormously influential text that emphasized the physiological approach to lung disease that had been established in the study of COPD. Bates and Christie recruited William ‘Whitey’ Thurlbeck, an American-trained South African pathologist, to McGill, in Quebec, and Thurlbeck soon afterwards established himself as the world’s leading expert on the pathology of COPD (7). Structure-function correlation was one of his strengths. In the early years, he had obtained lung function studies in virtually all patients who were scheduled to undergo surgery for coronary artery disease. These were largely older men with smoking histories who had a substantial perioperative mortality. When mortality occurred, Whitey studied their lungs and developed a unique case series. Peter Macklem’s early research involved forced expiration, noting that this was often accompanied by collapse (or compression) of major airways in normal subjects, but especially in subjects with diseased airways. This was achieved by a heroic procedure called a ‘pressure bronchogram’, with colleagues serving as subjects. He worked several years in Boston with Dr Jere Mead, developing the ‘equal pressure point’ theory of expiratory flow limitation, an extremely rewarding analytical technique that established the elastic recoil of the lung as an important determinant of maximum expiratory flow. Probably more importantly, he developed a method of measuring ‘peripheral’ (less than 2 mm diameter) airway resistance, then returned to Montreal, where he collaborated with Thurlbeck and a new trainee named Jim Hogg in studying peripheral airways in disease. They established that the major site of increased airway resistance in COPD was in the peripheral airways (8); it was later shown that peripheral airway lesions were characteristic of smokers. Thus, it was established that the airflow limitation characteristic of COPD was due to emphysema, or loss of lung recoil and/or peripheral airways disease. Because peripheral airways normally did not contribute greatly to the overall resistance, peripheral disease had to be substantial before overall flow limitation occurred, possibly making peripheral disease more difficult to detect with ordinary lung function tests (9). There then followed an intense exploration of a variety of new tests led by the Montreal group. These tests chiefly involved using gas distribution, such as closing volume, and tests measuring changes in maximum expiratory flow with changes in gas density, because airflow in major airways was turbulent and density-dependent, but this was not the case in the periphery. In fairness, this work contributed greatly to physiological knowledge, but less so to the clinical problem of COPD. The progress cited above brings us to (approximately) 1980. The pathology and pathophysiology of COPD were well understood, although its pathogenesis was not; for example, why did some smokers get the disease while others did not? We will return to these questions later. The next 20 years were notable for clinical trials in COPD, in which Canadian centres played a major role. The first of these was the Nocturnal Oxygen Therapy Trial, a multicentre effort sponsored by the National Institutes of Health (NIH) of the United States. Winnipeg, Manitoba, was one of six participating centres, eligible for obscure reasons having to do with the trial being funded as a contract. It compared a round-theclock (continuous) oxygen therapy with nocturnal-only oxygen in hypoxemic COPD patients. To the surprise of all concerned, there was nearly a twofold mortality benefit favouring the continuous treatment (10). A British study (11) simultaneously compared 15 h of oxygen a day with none, which also showed a substantial survival benefit with oxygen. The case was made. It is worth noting that the two studies involved a total of approximately 300 patients (200 in North America and 100 in the United Kingdom) and that the data acquired in these small cohorts have guided oxygen therapy ever since, something that sometimes confounds third-party payers. The NIH then sponsored a trial of intermittent positive pressure breathing (IPPB) as treatment in COPD, and Winnipeg was one of five participating centres. IPPB was controversial at

Objectives (1) To correlate structure (CT) with function in pulmonary tuberculosis (TB), and (2) to describe the evolution of structural and functional abnormalities when pulmonary TB is treated with directly observed therapy. Subjects and methods Twenty-five patients with drug-susceptible pulmonary TB, 15 cavitary and 10 noncavitary, were studied prospectively. Conventional CT and pulmonary function testing (spirometry, diffusing capacity, and arterial blood gases) were performed at baseline, and after 1 and 6 months of directly observed therapy. Results All but one patient with noncavitary miliary TB had CT evidence of endobronchial disease, and all patients with cavitary disease had coexistent reduced lung attenuation, the latter presumably a result of gas trapping, hypoxic vasoconstriction, and vascular injury. Functional impairment was minimal and in proportion to the number of diseased segments and cavitary volume. Bronchiectasis was significantly more likely to complicate cavitary than noncavitary disease (64 vs 11%; p Conclusions CT findings correlate well with function in pulmonary TB. Physiologic data were consistent with the concept that pulmonary TB is an endobronchial disease that causes parallel reductions in ventilation and perfusion. This concurrent involvement of both airways and contiguous pulmonary blood supply offers an explanation for the minimal respiratory limitation experienced by these patients despite often extensive lung disease. Supervised therapy of drug-susceptible disease results in minimal structural and functional residua.

The determinants of the response of the respiratory output to inspiratory flow rates (VI) were examined in awake normal subjects. Subjects were connected to a volume-cycle ventilator in the assist/control mode, and VI was increased in steps from 30 to 90 L/min and then back to 30 L/min. VI pattern was square, and all breaths were subject-triggered. In six subjects the effects of breathing route (nasal or mouth) and temperature and volume of inspired gas (Protocol A) and in 8 subjects the effects of airway anesthesia (upper and lower airways; Protocol B) on the response of respiratory output to varying VI were studied. In Protocol B, in order to calculate muscle pressure during inspiration (Pmus), respiratory system mechanics were measured using the interrupter method at end-inspiration. Independent of conditions studied, breathing frequency increased significantly and end-tidal concentration of CO2 decreased as VI increased. The response was graded and reversible and not affected by breathing route, temperature and volume of inspired gas, and airway anesthesia. With and without airway anesthesia (Protocol B), neural inspiratory and expiratory time and neural duty cycle, estimated from Pmus waveform, decreased significantly as VI increased. At all conditions studied, the rate of change in airway pressure prior to triggering the ventilator tended to increase as VI increased. The changes in timing and drive were nearly complete within the first two breaths after transition, with no evidence of adaptation during a given VI period. We conclude that VI exerts an excitatory effect on respiratory output which is independent of breathing route, temperature and volume of inspirate, and airway anesthesia. The response most likely is neural in origin, mediated through receptors not accessible to anesthesia, such as those located in the chest wall or below the airway mucosa.

The Lung Health Study (LHS) was a multicenter clinical trial of smoking intervention and inhaled bronchodilator in middleaged smokers with mild to moderate chronic obstructive pulmonary disease (1) that accumulated a large cohort of high-risk individuals and has monitored them for nearly 15 years. This article reviews results of the initial study and subsequent longterm follow-up, and some of the risk factors for rapid decline of lung function in the cohort. At 10 clinical centers in 1986–1988, the LHS recruited 5,887 smokers aged 35–59 years. Entry criteria included evidence of airway obstruction, that is, FEV1/FVC less than 0.70 and FEV1 55–90% of the predicted normal value, and a willingness to enter a smoking cessation program. People with other diseases and those being treated for lung disease were excluded. They were randomized into three groups: usual care (UC) participants were advised to stop smoking and followed; special intervention (SI) participants were enrolled in an intensive smoking cessation program (2), and half (SIA) were prescribed an inhaled bronchodilator (ipratropium bromide) and the other half (SIP) given placebo in a double-blind fashion. All participants were followed with annual spirometry for 5 years and SI participants were seen at least every 4 months to maintain compliance with the interventions. The main outcome measure, spirometry, was assessed with great care in a standardized fashion (3). Methacholine reactivity was measured at baseline and again at the end of 5 years. On entry, participants averaged 48 years of age, and 63% were male. They were heavy smokers, averaging more than 31 cigarettes per day, with more than 40 pack-years. Their FEV1 averaged 75% of the predicted normal (2.64 L) and increased little (0.110 L) with bronchodilator treatment. They demonstrated a surprising degree of methacholine reactivity, in that about one-third had a 20% decline in FEV1 with a methacholine dose of 5 mg/ml. Approximately 11 years after entry efforts were made to reexamine all of the original participants who were not known to be dead (4), and spirometry was repeated when possible.

Study objective Patients with moderate to severe COPD are frequently prescribed expensive and complicated therapies that require adjustments in usual activities of daily living. However, little is known about factors that are associated with adherence to such treatment. The objective of this study was to identify characteristics of patients who were adherent to long-term home nebulizer therapy. Design Patients were stratified into two adherence groups based on average minutes of nebulizer use each day. A logistic regression model was developed to predict adherence based on baseline variables. A questionnaire was administered to patients to assess reasons for adherence to therapy. Setting Five clinical centers in the United States and Canada. Participants Nine hundred eighty-five patients with moderate to severe COPD enrolled in the Intermittent Positive Pressure Breathing (IPPB) Trial. Interventions Long-term home IPPB and nebulizer therapy. Measurements and results Altogether 50.6% of patients were adherent, and 49.4% were nonadherent. Among baseline variables, good adherence was predicted by white race, married status, abstinence from cigarettes and alcohol, serum theophylline level ≥9 μg/mL, more severe dyspnea, and reduced FEV 1 (p Conclusions Sociodemographic, physiologic, and quality of life variables were associated with adherence to long-term nebulizer therapy. (CHEST 1995; 108:394-400)

Objective: To assess changes in the severity of physician-diagnosed asthma between 1983 and 1988. Design: Cross-sectional studies examining the frequency of markers of asthma severity: hospitalizations, ICU admissions, hospital emergency department visits, multiple physician contacts, and referrals to specialists in patients aged 0 to 14 years, 14 to 34 years, and ≥35 years separately. Setting: Physicians' claims data from the universal Provincial Health Insurance Plan for fiscal years 1983 and 1988. Patients: All patients with the diagnosis of asthma, bronchitis, and COPD identified from the Manitoba Health database. Measurements: The markers of severity were related to the prevalence of patients seeing a physician and receiving a diagnostic label of asthma, COPD, or bronchitis. Results: The number of patients with physician-diagnosed asthma increased by 36.4% over the 5 years. In 1983, 11% of asthmatics were hospitalized during the year and 8% were hospitalized in 1988 (–2.5%; 95% confidence interval [CI], –3.2 to –1.8%). During both years, about 75% of the patients hospitalized were in hospital once only. Mean and median duration of hospital stay declined. The percentage of asthmatics seen in the hospital emergency departments declined slightly in all age groups, the total being 21% in 1983 and 18% in 1988 (–3.5%; 95% CI, –4.5 to –2.5%). About one third of the patients with asthma were seen only once by a physician during both of the years examined, 43 to 45% of them being seen on three or more occasions during both years. Referrals to specialists for all asthmatics increased from 12 to 14% (1.9%; 95% CI, 1.0 to 2.8%) from 1983 to 1988. This was almost entirely due to an increase from 11 to 16% (5.1%; 95% CI, 4.0 to 6.2%) in the youngest age group, an increase not accompanied by an increase in any other marker of severity. Changes in asthma severity were similar to changes in the severity in patients with bronchitis and COPD. Conclusion: No increase in severity of asthma was seen between 1983 and 1988, but the prevalence of the diagnostic label of asthma increased substantially.

We examined the effects of the dopamine blocker haloperidol (H) on the ventilatory response to sustained hypoxia in awake cats. Ventilation (VE) was measured plethysmographically, and end-tidal PO2 (PETO2) and PCO2 were measured by sampling tracheal gas. Measurements were made before, during, and after 30 min of isocapnic hypoxia after pretreatment with 0.1 mg/kg of H and placebo (P). Experimental runs were conducted on separate days with the P day being first. Two levels of hypoxia were employed. Six cats were studied at a PETO2 of approximately 61 Torr, and six cats were studied at a PETO2 of approximately 41 Torr. In all experiments, isocapnia was maintained and end-tidal PCO2 did not differ on the H and P days. With mild hypoxia after P, VE increased to 137% of air breathing control in the first 5 min of hypoxia and then declined to 102% of control at 25 min of hypoxia. Results on the H day were similar. With more severe hypoxia after P, VE increased to 173% of control at 5 min and then declined to 127% of control. With H, VE increased to 172% of control in the first 5 min and then declined to 149% of control at 25 min. After 25 min of more severe hypoxia, both VE and tidal volume were significantly greater with H than with P (P < 0.05). H reduced the ventilatory decline observed with more severe hypoxia but had no effect on the ventilatory decline in milder hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

In normal conscious humans, when a brief hypoxic ventilatory stimulus is followed immediately by breathing 100% O2, ventilation during hyperoxia gradually declines to baseline prehypoxic levels without an undershoot. During the decline, ventilation is greater than baseline in the absence of hypoxia and hypercapnia. This has been interpreted as evidence of decay of short-term potentiation (STP) or afterdischarge. It is not known whether the intensity of the stimulus that activates STP influences the time course of its decay. Therefore we studied STP decay in nine normal adults after administration of placebo (P) and almitrine (A) in a single-blind manner on 2 separate days. On each day, three runs consisting of 45 s of isocapnic hypoxia (end-tidal PO2 = 55 mm Hg) followed by 2 min of hyperoxia were conducted while ventilation (VI) was measured breath by breath. Baseline VT did not differ between A and P, but at the end of hypoxia, VI with A was 169 +/- 14% (SE) of baseline while VI with P was 132 +/- 7% of baseline (p0.05). Immediately after hyperoxia was instituted, VI fell abruptly, the fall being 36% of baseline for A and 15% for P. This probably represented the withdrawal of peripheral chemoreceptor input. Thereafter, VI declined slowly toward baseline, and the time course of this decline did not differ between P and A. Our results indicate that within the limits we studied, the increase of the intensity of the discharge of the peripheral chemoreceptors during hypoxia does not influence STP decay.

Some have suggested that chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown. Using quantitative polymerase chain reaction (qPCR), we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS). The subjects were followed for approximately 7.5 years during which time their vital status, FEV(1) and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy "mid-life" volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy "mid-life" volunteers (p

Tillie-Louise Hackett1,2,*, Dorota Stefanowicz1,*, Farzian Aminuddin1, Don D Sin1, John E Connett3, Nicholas R Anthonisen4, Peter D Paré1, Andrew J Sandford11University of British Columbia, James Hogg Research Laboratories, St Paul's Hospital, Division of Respirology, Department of Medicine, 2Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, BC, Canada; 3School of Public Health, University of Minnesota, Minneapolis, MN, USA; 4Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada*These authors contributed equally to this workBackground: The objective of this study was to determine if gene-environment interactions between cigarette smoking and interleukin-6 (IL6), interferon-γ (IFNG), interleukin-1β (IL1B), or interleukin-1 receptor antagonist (IL1RN) single nucleotide polymorphisms are associated with lung function decline and cardiovascular disease in chronic obstructive pulmonary disease (COPD).Methods: Single nucleotide polymorphisms (SNPs) in IL6, IFNG, IL1B, and IL1RN were genotyped in the Lung Health Study and correlated with rate of decline of forced expiratory volume in 1 second (FEV1) over 5 years, baseline FEV1, serum protein levels, cardiovascular disease, and interactions with smoking.Results: The IL6 rs2069825 single nucleotide polymorphism was associated with the rate of decline of prebronchodilator FEV1 (P = 0.049), and was found to have a significant interaction (P = 0.004) with mean number of cigarettes smoked per day. There was also a significant interaction of IFNG rs2069727 with smoking on prebronchodilator (P = 0.008) and postbronchodilator (P = 0.01) FEV1. The IL6 polymorphism was also associated with cardiovascular disease in heterozygous individuals (P = 0.044), and was found to have a significant interaction with smoking (P = 0.024). None of the genetic variants were associated with their respective serum protein levels.Conclusion: The results suggest interactions of IL6 rs2069825 and IFNG rs2069727 single nucleotide polymorphisms with cigarette smoking on measures of lung function. The IL6 rs2069825 single nucleotide polymorphism also interacted with smoking to affect the risk of cardiovascular disease in COPD patients.Keywords: gene-environment interactions, interleukin-6, forced expiratory volume in one second, cardiovascular disease, chronic obstructive pulmonary disease

The reported prevalence of pulmonary nontuberculous mycobacteria (NTM) infections is increasing.To determine the 'isolation prevalence' of NTM in 2007 and compare it with previously published research that examined the increasing rates of isolation of NTM from clinical pulmonary specimens between 1997 and 2003.Isolation prevalence was investigated retrospectively by reviewing a cohort of all positive pulmonary NTM culture results from the Tuberculosis and Mycobacteriology Laboratory, Public Health Laboratory (Toronto, Ontario) in 2007, which identifies at least 95% of NTM isolates in Ontario. Isolation prevalence was calculated as the number of persons with a pulmonary isolate in a calendar year divided by the contemporary population and expressed per 100,000 population. Changes in isolation prevalence from previous years were assessed for statistical significance using generalized linear models with a negative binomial distribution.In 2007, 4160 pulmonary isolates of NTM were collected from 2463 patients. The isolation prevalence of all species (excluding Mycobacterium gordonae) was 19 per 100,000 population in 2007 - an increase from previous observations reported for Ontario - corresponding to an average annual increase of 8.5% from 1997 to 2007 (P0.0001). Average annual increases in isolation prevalence of Mycobacterium avium complex (8.8%, P0.0001) and Mycobacterium xenopi (7.3%, P=0.0005) were largely responsible for the overall increase, while prevalence rates of rapidly growing mycobacteria remained relatively stable.The isolation prevalence of pulmonary NTM continues to increase significantly in Ontario, supporting the belief that pulmonary NTM disease is increasingly common.