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1.  The association between airflow obstruction and radiologic change by tuberculosis 
Journal of Thoracic Disease  2014;6(5):471-476.
Introduction
Cigarette smoking is the most commonly encountered risk factor for chronic obstructive pulmonary disease (COPD). However, it is not the only one and there is consistent evidence from epidemiologic studies that nonsmokers may develop chronic airflow limitation. A history of tuberculosis has recently been found to be associated with airflow obstruction in adults older than 40 years. The aim of this study was to evaluate the association between the radiologic changes by tuberculosis and airflow obstruction in a population based sample.
Methods
A nationwide COPD prevalence survey was conducted. We compared the prevalence of airflow obstruction according to the presence of the radiologic change by the tuberculosis.
Results
We analyzed 1,384 subjects who participated in the nationwide Korean COPD survey. All subjects were older than 40 years and took the spirometry and simple chest radiography. We defined the airflow obstruction as FEV1/FVC <0.7. A total of 149 (10.8%) subjects showed airflow obstruction. A total of 167 (12.1%) subjects showed radiologic change by tuberculosis. Among these 167 subjects, 44 (26.3%) had airflow obstruction. For the subjects without radiologic change by tuberculosis, the prevalence of airflow obstruction was only 8.6%. The unadjusted odds ratio for airflow obstruction according to the radiologic change was 3.788 (95% CI: 2.544-5.642).
Conclusions
The radiologic change by tuberculosis was associated with airflow obstruction.
doi:10.3978/j.issn.2072-1439.2014.04.02
PMCID: PMC4014992  PMID: 24822105
Chronic obstructive pulmonary disease (COPD); tuberculosis; risk factor; airflow obstruction
2.  Lung Function in Young Adults Predicts Airflow Obstruction 20 Years Later 
The American journal of medicine  2010;123(5):468.e1-468.e7.
Rationale
The burden of obstructive lung disease is increasing, yet there are limited data on its natural history in young adults.
Objectives
To determine in a prospective cohort of generally healthy young adults the influence of early adult lung function on the presence of airflow obstruction in middle age.
Methods
Longitudinal study of 2,496 adults who were 18-30 years of age at entry, did not report having asthma, and returned at Year 20. Airflow obstruction was defined as an FEV1/FVC ratio less than the lower limit of normal.
Measurements and Main Results
Airflow obstruction was present in 6.9% and 7.8% of participants at Years 0 and 20. Less than 10% of participants with airflow obstruction self-reported COPD. In cross sectional analyses airflow obstruction was associated with less education, smoking, and self-reported COPD. Low FEV1 and FEV1/FVC and airflow obstruction in young adults were associated with low lung function and airflow obstruction 20 years later. Of those with airflow obstruction at Year 0, 52% had airflow obstruction 20 years later. The FEV1/FVC at Year 0 was highly predictive of airflow obstruction 20 years later (c-statistic 0.91; 95% CI 0.89-0.93). The effect of cigarette smoking on lung function decline with age was most evident in young adults with pre-existing airflow obstruction.
Conclusions
Airflow obstruction is mostly unrecognized in young and middle age adults. A low FEV1, low FEV1/FVC and airflow obstruction in young adults, in addition to smoking, are highly predictive of low lung function and airflow obstruction in middle age.
doi:10.1016/j.amjmed.2009.07.037
PMCID: PMC2858051  PMID: 20399325
Airflow obstruction; CARDIA; chronic obstructive pulmonary disease; COPD; natural history
3.  Passive smoking and chronic obstructive pulmonary disease: cross-sectional analysis of data from the Health Survey for England 
BMJ Open  2011;1(2):e000153.
Objectives
There is increasing evidence that passive smoking is associated with chronic respiratory diseases, but its association with chronic obstructive pulmonary disease (COPD) requires more study. In this cross-sectional analysis of data from 3 years of the Health Survey for England, the association between passive smoking exposure and risk of COPD is evaluated.
Design
Cross-sectional analysis of the 1995, 1996 and 2001 Health Surveys for England including participants of white ethnicity, aged 40+ years with valid lung function data. COPD was defined using the lower limit of normal spirometric criteria for airflow obstruction. Standardised questions elicited self-reported information on demography, smoking history, ethnicity, occupation, asthma and respiratory symptoms (dyspnoea, chronic cough, chronic phlegm, wheeze). Passive smoking was measured by self-report of hours of exposure to cigarette smoke per week.
Results
Increasing passive smoke exposure was independently associated with increased risk of COPD, with adjusted OR 1.05 (95% CI 0.93 to 1.18) for 1–19 h and OR 1.18 (95% CI 1.01 to 1.39) for 20 or more hours of exposure per week. Similar patterns (although attenuated and non-significant) were observed among never smokers. More marked dose–response relationships were observed between passive smoking exposure and respiratory symptoms, but the most marked effects were on the development of clinically significant COPD (airflow obstruction plus symptoms), where the risk among never smokers was doubled (OR 1.98 (95% CI 1.03 to 3.79)) if exposure exceeded 20 h/week.
Conclusion
This analysis adds weight to the evidence suggesting an association between passive smoking exposure and COPD.
Article summary
Article focus
Passive exposure to cigarette smoke is established as an important independent risk factor for the development of chronic conditions such as heart disease and lung cancer.
Although there is growing evidence implicating passive smoking in asthma and other respiratory diseases, the evidence for its effect on chronic obstructive pulmonary disease (COPD) is inconsistent.
Using cross-sectional data from the annual Health Survey for England, we examined the association between self-reported exposure to passive smoking and COPD.
Key messages
We have demonstrated a significant dose–response relationship between hours of exposure to passive smoking and increasing risk of COPD.
The most marked effects were observed on the development of clinically significant COPD (airflow obstruction plus symptoms), where the risk among never smokers was doubled (OR 1.98 (95% CI 1.03 to 3.79)) if exposure exceeded 20 h/week.
Passive smoking is prevalent worldwide, and even after the 2007 public smoking ban in the UK, 20% of the adult English population are still exposed to up to 20 h of passive smoking per week, with 5% exposed to more than 20 h/week; further measures are needed to investigate and reduce exposures in the home and elsewhere.
Strengths and limitations of this study
Our study has the advantage of being a large sample representative of the English population (>21 000 participants), conducted over 3 separate years, with a standardised protocol and objective measure of lung function.
However, due to the cross-sectional nature of the design, temporal associations cannot necessarily be inferred.
The Health Survey for England was not designed for the specific analyses presented in this paper, and thus some of the measures are crude.
Self-reported passive smoke exposure is only a proxy for true exposure levels, but is accepted as the most practical method of assessment.
doi:10.1136/bmjopen-2011-000153
PMCID: PMC3191589  PMID: 22021874
4.  Clinical Characteristics of Asthma Combined with COPD Feature 
Yonsei Medical Journal  2014;55(4):980-986.
Purpose
In clinical practice, some patients with asthma show incompletely reversible airflow obstruction, resembling chronic obstructive pulmonary disease (COPD). The aim of this study was to analyze this overlap phenotype of asthma with COPD feature.
Materials and Methods
A total of 256 patients, over the age of 40 years or more with a diagnosis of asthma, based on either 1) positive response to bronchodilator: >200 mL forced expiratory volume in 1 s (FEV1) and >12% baseline or 2) positive methacholine or mannitol provocation test, were enrolled. Among the asthma patients, we defined the overlap group with incompletely reversible airflow obstruction [postbronchodilator FEV1/forced vital capacity (FVC) <70] at the initial time of admission and continuing airflow obstruction after at least 3 months follow up. We evaluated clinical features, serum eosinophil counts, serum total immunoglobulin (Ig) E with allergy skin prick test, spirometry, methacholine or mannitol provocation challenges and bronchodilator responses, based on their retrospective medical record data. All of the tests mentioned above were performed within one week.
Results
The study population was divided into two groups: asthma only (62%, n=159, postbronchodilator FEV1/FVC ≥70) and overlap group (38%, n=97, postbronchodilator FEV1/FVC <70). The overlap group was older, and contained more males and a higher percentage of current or ex-smokers than the asthma only group. Significantly lower FEV1 and higher total lung capacity, functional residual capacity, and residual volume were observed in the overlap group. Finally, significantly lower serum eosinophil count and higher IgE were seen in the overlap group.
Conclusion
Our results showed that the overlap phenotype was older, male asthmatic patients who have a higher lifetime smoking intensity, more atopy and generally worse lung function.
doi:10.3349/ymj.2014.55.4.980
PMCID: PMC4075403  PMID: 24954327
Asthma; chronic obstructive pulmonary disease; overlap; airway hyperresponsiveness
5.  Difference in airflow obstruction between Hispanic and non-Hispanic white female smokers 
COPD  2008;5(5):274-281.
Rationale
Smoking-related respiratory diseases are a major cause of morbidity and mortality. However, the relationship between smoking and respiratory disease has not been well-studied among ethnic minorities in general and among women in particular.
Objective
The objective of this cross-sectional study was to evaluate the risk of airflow obstruction and to assess lung function among Hispanic and non-Hispanic white (NHW) female smokers in a New Mexico cohort.
Methods
Participants completed a questionnaire detailing smoking history and underwent spirometry testing. Outcomes studied included airflow obstruction, selected lung function parameters, and chronic mucus hyper-secretion. Chi square, logistic, and linear regression techniques were utilized.
Main findings
Of the 1,433 eligible women participants, 248 (17.3%) were Hispanic; and 319 had airflow obstruction (22.3%). Hispanic smokers were more likely to be current smokers, and report lower pack-years of smoking, compared to NHW smokers (p < 0.05 for all analyses). Further, Hispanic smokers were at a reduced risk of airflow obstruction compared to NHW smokers, with an O.R. of 0.51, 95% C.I. 0.34, 0.78 (p = 0.002) after adjustment for age, BMI, pack-years and duration of smoking, and current smoking status. Following adjustment for covariates, Hispanic smokers also had a higher mean absolute and percent predicted post-bronchodilator FEV1/FVC ratio, as well as higher mean percent predicted FEV1 (p < 0.05 for all analyses).
Principal conclusions
Hispanic female smokers in this New Mexico-based cohort had lower risk of airflow obstruction and better lung function than NHW female smokers. Further, smoking history did not completely explain these associations.
doi:10.1080/15412550802363345
PMCID: PMC3616889  PMID: 18972275
Hispanic ethnicity; Smokers; Airflow obstruction; Pulmonary function; Chronic mucus hyper-secretion; Women
6.  Asthma and irreversible airflow obstruction. 
Thorax  1984;39(2):131-136.
To determine whether asthma alone can cause irreversible airflow obstruction 42 men and 47 women with chronic asthma (mean duration 22 (SD 13) years) without evidence of other disease likely to cause irreversible airflow obstruction were treated with theophylline orally and a beta agonist both orally and by inhalation for four weeks. After two weeks of treatment the FEV1 was less than 85% of the predicted normal value (%P) in 48 patients and these individuals then received prednisolone 0.6 mg/kg/day for two weeks. Duration and severity of asthma and smoking history were quantified by questionnaire; 38 patients were current smokers or ex-smokers. FEV1 was measured at 0, 2, and 4 weeks. The mean difference between the best FEV1 during the study and the predicted normal value was 0.29 l (p less than 0.001); FEV1 %P decreased with age (r = -0.30, p less than 0.01) and with the duration (r = -0.47, p less than 0.001) and severity (r = -0.55, p less than 0.001) of asthma. Similar findings were noted when the results for non-smokers and those whose asthma started in adult life were analysed separately. We conclude that asthma alone can cause irreversible airflow obstruction and that the degree of obstruction is a function of the duration and severity of previous asthma. The results suggest the possibility that irreversible airflow obstruction in asthma may be preventable by minimising the degree of persistent asthma.
PMCID: PMC459739  PMID: 6701824
7.  Estimating population prevalence of potential airflow obstruction using different spirometric criteria: a pooled cross-sectional analysis of persons aged 40–95 years in England and Wales 
BMJ Open  2014;4(7):e005685.
Objectives
Consistent estimation of the burden of chronic obstructive pulmonary disease (COPD) has been hindered by differences in methods, including different spirometric cut-offs for impaired lung function. The impact of different definitions on the prevalence of potential airflow obstruction, and its associations with key risk factors, is evaluated using cross-sectional data from two nationally representative population surveys.
Design
Pooled cross-sectional analysis of Wave 2 of the UK Household Longitudinal Survey and the Health Survey for England 2010, including 7879 participants, aged 40–95 years, who lived in England and Wales, without diagnosed asthma and with good-quality spirometry data. Potential airflow obstruction was defined using self-reported physician-diagnosed COPD; a fixed threshold (FT) forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio <0.7 and an age-specific, sex-specific, height-specific and ethnic-specific lower limit of normal (LLN). Standardised questions elicited self-reported information on demography, smoking history, ethnicity, occupation, respiratory symptoms and cardiovascular disease.
Results
Consistent across definitions, participants classed with obstructed airflow were more likely to be older, currently smoke, have higher pack-years of smoking and be engaged in routine occupations. The prevalence of airflow obstruction was 2.8% (95% CI 2.3% to 3.2%), 22.2% (21.2% to 23.2%) and 13.1% (12.2% to 13.9%) according to diagnosed COPD, FT and LLN, respectively. The gap in prevalence between FT and LLN increased in older age groups. Sex differences in the risk of obstruction, after adjustment for key risk factors, was sensitive to the choice of spirometric cut-off, being significantly higher in men when using FT, compared with no significant difference using LLN.
Conclusions
Applying FT or LLN spirometric cut-offs gives a different picture of the size and distribution of the disease burden. Longitudinal studies examining differences in unscheduled hospital admissions and risk of death between FT and LLN may inform the choice as to the best way to include spirometry in assessments of airflow obstruction.
doi:10.1136/bmjopen-2014-005685
PMCID: PMC4120415  PMID: 25056983
Epidemiology; Public Health; Primary Care; Respiratory Medicine (see Thoracic Medicine)
8.  Bronchial reactivity and airflow obstruction in rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1994;53(8):511-514.
OBJECTIVES--To investigate the prevalence of airways obstruction and bronchial reactivity to inhaled methacholine in rheumatoid arthritis patients and unselected controls. The control population consisted of patients attending the rheumatology department for minor degenerative joint problems. METHODS--One hundred patients with rheumatoid arthritis (RA) [72 (72%) women, 28 (28%) men; mean (SD) age 58 (10) years] and fifty controls [30 (60%) women, 20 (40%) men; mean (SD) age 56 (9) years] were studied. Detailed medical, smoking and drug histories were taken; skin prick tests were performed to assess atopy and chest and hand radiographs were performed. Spirometry, flow volume loops and gas transfer factor measurement were performed to detect airflow obstruction and methacholine inhalation tests were carried out to assess bronchial reactivity. RESULTS--There was no significant difference between rheumatoid arthritis patients and the controls in age, sex, smoking status and atopy on skin prick testing (p < 0.05). A significantly higher number of patients with RA had a history of wheeze compared with the controls (18% v 4%, p < 0.05). FEV1, FVC, FEV1/FVC, FEF25-75%, FEF25%, FEF50% and FEF75% were all significantly lower in the rheumatoid arthritis group (p < 0.05). A significantly higher number of patients with RA compared with controls showed bronchial reactivity to inhaled methacholine [55 (55%) v 8 (16%), p < 0.05]. FEV1, FVC, FEV1/FVC, FEF25-75%, FEF25%, FEF50% and FEF75% were all significantly lower among the patients with RA achieving PD20 FEV1 to inhaled methacholine (p < 0.05). CONCLUSION--In unselected rheumatoid arthritis patients both airflow obstruction and bronchial reactivity are significantly increased compared with controls.
PMCID: PMC1005390  PMID: 7944635
9.  Smoking Inhibits the Frequency of Bronchovascular Bundle Thickening in Sarcoidosis 
Academic radiology  2011;18(7):885-891.
Rationale/Objectives
Smoking has been associated with decreased incidence and prevalence of sarcoidosis, but few studies have evaluated effects of smoking on clinical parameters of the disease. The objectives were to determine the association of smoking with radiographic patterns and to evaluate the associations of these smoking-related radiographic patterns on airflow obstruction in sarcoidosis.
Methods
Clinical data and CT scans of 124 patients with sarcoidosis were reviewed. CT scans were assessed for lymph nodes, nodules, bronchiectasis, bronchovascular bundle thickening, displaced hilum, fibrosis, ground glass, emphysema, pleural changes, and alveolar opacities. CT patterns were compared between patients with and without a history of smoking. The effect of smoking on the associations between radiographic patterns and airflow obstruction was assessed with multivariable analysis.
Results
Smokers had less frequency of bronchovascular bundle thickening than nonsmokers (11/38 subjects(29%) vs. 50/86 subjects(58%),p=0.003) and more emphysema (7/38 subjects(18%) vs. 1/86 subjects(1%),p=0.001). Patients who had bronchovascular bundle thickening were less likely to have ever smoked (11/61 subjects(18%) vs. 27/63 subjects(43%), p=0.003) or be current smokers (4/61 subjects(7%) vs. 15/63 subjects(24%),p=0.008). Age (p=0.003) and bronchovascular bundle thickening (p=0.02) were independent predictors of airflow obstruction. There were no differences in smoking history between patients with airflow obstruction versus those without (10/37 subjects(27)% vs. 28/87 subjects(32%),p=0.63).
Conclusions
In patients with sarcoidosis, smoking is associated with decreased frequency of bronchovascular bundle thickening, a very important clinical manifestation of the lung disease. Further, bronchovascular bundle thickening and age are the only independent predictors of airflow obstruction, and smoking does not confound these associations.
doi:10.1016/j.acra.2011.02.015
PMCID: PMC3115466  PMID: 21530329
Smoking; CT scan; X-ray; Sarcoidosis; Airway Obstruction; Granuloma
10.  Bronchial responsiveness to methacholine in chronic bronchitis: relationship to airflow obstruction and cold air responsiveness. 
Thorax  1984;39(12):912-918.
The response to inhaled methacholine is increased in patients with chronic airflow obstruction, but it is not known whether this is due to true hyperresponsiveness or is a result of the airflow obstruction. In asthmatics the response to methacholine correlates with the bronchoconstriction produced by hyperventilation of cold dry air. We studied 27 patients with a history of smoking and chronic bronchitis with a range of severity of airflow obstruction. Bronchial responses to methacholine (expressed as the provocation concentration causing a fall in FEV1 of 20%-PC20) and isocapnic hyperventilation of cold dry air were measured. In 19 patients the PC20 was less than 8 mg/ml (that is, in the asthmatic range) but only three developed bronchoconstriction in response to hyperventilation. There was a linear correlation between the log PC20 and the FEV1 (r = 0.86, p less than 0.001). The results suggest that in patients with chronic airflow obstruction the response to methacholine is determined by the degree of airflow obstruction, and cannot be used in the diagnosis of asthma in the absence of additional information.
PMCID: PMC459952  PMID: 6393416
11.  Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction 
Wilk, Jemma B. | Shrine, Nick R. G. | Loehr, Laura R. | Zhao, Jing Hua | Manichaikul, Ani | Lopez, Lorna M. | Smith, Albert Vernon | Heckbert, Susan R. | Smolonska, Joanna | Tang, Wenbo | Loth, Daan W. | Curjuric, Ivan | Hui, Jennie | Cho, Michael H. | Latourelle, Jeanne C. | Henry, Amanda P. | Aldrich, Melinda | Bakke, Per | Beaty, Terri H. | Bentley, Amy R. | Borecki, Ingrid B. | Brusselle, Guy G. | Burkart, Kristin M. | Chen, Ting-hsu | Couper, David | Crapo, James D. | Davies, Gail | Dupuis, Josée | Franceschini, Nora | Gulsvik, Amund | Hancock, Dana B. | Harris, Tamara B. | Hofman, Albert | Imboden, Medea | James, Alan L. | Khaw, Kay-Tee | Lahousse, Lies | Launer, Lenore J. | Litonjua, Augusto | Liu, Yongmei | Lohman, Kurt K. | Lomas, David A. | Lumley, Thomas | Marciante, Kristin D. | McArdle, Wendy L. | Meibohm, Bernd | Morrison, Alanna C. | Musk, Arthur W. | Myers, Richard H. | North, Kari E. | Postma, Dirkje S. | Psaty, Bruce M. | Rich, Stephen S. | Rivadeneira, Fernando | Rochat, Thierry | Rotter, Jerome I. | Artigas, María Soler | Starr, John M. | Uitterlinden, André G. | Wareham, Nicholas J. | Wijmenga, Cisca | Zanen, Pieter | Province, Michael A. | Silverman, Edwin K. | Deary, Ian J. | Palmer, Lyle J. | Cassano, Patricia A. | Gudnason, Vilmundur | Barr, R. Graham | Loos, Ruth J. F. | Strachan, David P. | London, Stephanie J. | Boezen, H. Marike | Probst-Hensch, Nicole | Gharib, Sina A. | Hall, Ian P. | O’Connor, George T. | Tobin, Martin D. | Stricker, Bruno H.
Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.
Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.
Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV1 and its ratio to FVC (FEV1/FVC) both less than their respective lower limits of normal as determined by published reference equations.
Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV1/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.
Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
doi:10.1164/rccm.201202-0366OC
PMCID: PMC3480517  PMID: 22837378
chronic obstructive pulmonary disease; single-nucleotide polymorphism; genes
12.  Wheat flour sensitisation and airways disease in urban bakers. 
A total of 176 bakers and 24 subjects employed as bread slicers and wrappers were studied to examine the effect of occupational category on respiratory symptoms, ventilatory capacity, non-specific bronchial reactivity, and prick skin test responses to wheat and common allergens. Bakers had a greater prevalence of attacks of wheeze and dyspnoea and more frequently considered that work affected their chests than did slicers and wrappers. Bakers with a history of asthma with onset since starting work in a bakery had a greater prevalence of chronic cough and sputum, increased bronchial reactivity, and positive prick skin test responses to wheat and common allergens than other bakers. There was a significant association between the frequency of positive prick skin tests to wheat and common allergens, suggesting that prior atopy facilitates sensitisation to cereal antigens. The frequency of positive prick skin responses to common allergens, however, declined with increasing baking duration whereas the frequency of positive skin responses to wheat increased with increasing baking duration, suggesting that subjects who were sensitised to common allergens were leaving the industry whereas subjects who stayed in the industry increased their risk of developing sensitisation to wheat. Oven handlers had a greater prevalence of attacks of wheeze and dyspnoea and more frequently considered that work affected their chests than either dough makers or general bakers. They also had a greater prevalence of positive prick skin test responses to wheat than dough makers or general bakers. Oven handlers also had a lower mean standardised casual FEV1 than either general bakers or dough makers. Thus oven handlers appear to have a greater risk of developing respiratory allergy and airflow obstruction than bakers in other occupational categories.
PMCID: PMC1009368  PMID: 6498109
13.  Pulmonary effects of passive smoking: the Indian experience 
Tobacco Induced Diseases  2002;1(2):129-136.
There are only a few studies done on pulmonary effects of passive smoking from India, which are summarized in this paper. Several vernacular tobacco products are used in India, bidis (beedis) being the commonest form of these. Bidis contain a higher concentration of nicotine and other tobacco alkaloids compared to the standard cigarettes (e.g., the sum of total nicotine and minor tobacco alkaloids was 37.5 mg in bidi compared to 14–16 mg in Indian or American cigarettes in one study). A large study performed on 9090 adolescent school children demonstrated environmental tobacco smoke (ETS) exposure to be associated with an increased risk of asthma. The odds ratio for being asthmatic in ETS-exposed as compared to ETS-unexposed children was 1.78 (95% CI: 1.33–2.31). Nearly one third of the children in this study reported non-specific respiratory symptoms and the ETS exposure was found to be positively associated with the prevalence of each symptom. Passive smoking was also shown to increase morbidity and to worsen the control of asthma among adults. Another study demonstrated exposure to ETS was a significant trigger for acute exacerbation of asthma. Increased bronchial hyper-responsiveness was also demonstrated among the healthy nonsmoking adult women exposed to ETS. Passive smoking leads to subtle changes in airflow mechanics. In a study among 50 healthy nonsmoking women passively exposed to tobacco smoke and matched for age with 50 unexposed women, forced expiratory volume in first second (FEV1) and peak expiratory flow (PEF) were marginally lower among the passive smokers (mean difference 0.13 L and 0.20 L-1, respectively), but maximal mid expiratory flow (FEF25–75%), airway resistance (Raw) and specific conductance (sGaw) were significantly impaired. An association between passive smoking and lung cancer has also been described. In a study conducted in association with the International Agency for Research on Cancer, the exposure to ETS during childhood was strongly associated with an enhanced incidence of lung cancer (OR = 3.9, 95% CI 1.9–8.2). In conclusions several adverse pulmonary effects of passive smoking, similar to those described from the western and developed countries, have been described from India.
doi:10.1186/1617-9625-1-2-129
PMCID: PMC2671649  PMID: 19570253
14.  Pulmonary effects of passive smoking: the Indian experience 
Tobacco Induced Diseases  2002;1(1):10.
There are only a few studies done on pulmonary effects of passive smoking from India, which are summarized in this paper. Several vernacular tobacco products are used in India, bidis (beedis) being the commonest form of these. Bidis contain a higher concentration of nicotine and other tobacco alkaloids compared to the standard cigarettes (e.g., the sum of total nicotine and minor tobacco alkaloids was 37.5 mg in bidi compared to 14–16 mg in Indian or American cigarettes in one study). A large study performed on 9090 adolescent school children demonstrated environmental tobacco smoke (ETS) exposure to be associated with an increased risk of asthma. The odds ratio for being asthmatic in ETS-exposed as compared to ETS-unexposed children was 1.78 (95% CI: 1.33–2.31). Nearly one third of the children in this study reported non-specific respiratory symptoms and the ETS exposure was found to be positively associated with the prevalence of each symptom. Passive smoking was also shown to increase morbidity and to worsen the control of asthma among adults. Another study demonstrated exposure to ETS was a significant trigger for acute exacerbation of asthma. Increased bronchial hyper-responsiveness was also demonstrated among the healthy nonsmoking adult women exposed to ETS. Passive smoking leads to subtle changes in airflow mechanics. In a study among 50 healthy nonsmoking women passively exposed to tobacco smoke and matched for age with 50 unexposed women, forced expiratory volume in first second (FEV1) and peak expiratory flow (PEF) were marginally lower among the passive smokers (mean difference 0.13 L and 0.20 L-1, respectively), but maximal mid expiratory flow (FEF25–75%), airway resistance (Raw) and specific conductance (sGaw) were significantly impaired. An association between passive smoking and lung cancer has also been described. In a study conducted in association with the International Agency for Research on Cancer, the exposure to ETS during childhood was strongly associated with an enhanced incidence of lung cancer (OR = 3.9, 95% CI 1.9–8.2). In conclusions several adverse pulmonary effects of passive smoking, similar to those described from the western and developed countries, have been described from India.
doi:10.1186/1617-9625-1-10
PMCID: PMC2669550
15.  Perseverant, non-indicated treatment of obese patients for obstructive lung disease 
Background
Bronchodilators are a mainstay of treatment for patients with airflow obstruction. We hypothesized that patients with obesity and no objective documentation of airflow obstruction are inappropriately treated with bronchodilators.
Methods
Spirometric results and medical records of all patients with body mass index >30 kg/m2 who were referred for testing between March 2010 and August 2011 were analyzed.
Results
155 patients with mean age of 52.6 ± (SE)1.1 y and BMI of 38.7 ± 0.7 kg/m2 were studied. Spirometry showed normal respiratory mechanics in 62 (40%), irreversible airflow obstruction in 36 (23.2%), flows suggestive of restriction in 35 (22.6%), reversible obstruction, suggestive of asthma in 11 (7.1%), and mixed pattern (obstructive and restrictive) in 6 (3.9%). Prior to testing, 45.2% (28 of 62) of patients with normal spirometry were being treated with medications for obstructive lung diseases and 33.9% (21 of 62) continued them despite absence of airflow obstruction on spirometry. 60% (21 of 35) of patients with a restrictive pattern in their spirometry received treatment for obstruction prior to spirometry and 51.4% (18 of 35) continued bronchodilator therapy after spirometric testing. There was no independent association of non-indicated treatment with spirometric results, age, BMI, co-morbidities or smoking history. All patients with airflow obstruction on testing who were receiving bronchodilators before spirometry continued to receive them after testing.
Conclusion
A substantial proportion of patients with obesity referred for pulmonary function testing did not have obstructive lung disease, but were treated nonetheless, before and after spirometry demonstrating absence of airway obstruction.
doi:10.1186/1471-2466-13-68
PMCID: PMC4222837  PMID: 24266961
Spirometry; Pulmonary function; Obesity; Asthma; Airflow obstruction; Restriction
16.  The Association of Pipe and Cigar Use with Cotinine Levels, Lung Function and Airflow Obstruction: a Cross-sectional Study 
Annals of internal medicine  2010;152(4):201-210.
Background
Cigarette smoking is the major cause of chronic obstructive pulmonary disease but studies on the contribution of other smoking techniques are sparse.
Objective
We hypothesized that pipe and cigar smoking was associated with elevated cotinine levels, decrements in lung function and increased odds of airflow obstruction.
Design
Cross-sectional study.
Setting
Population-based sample from six US communities.
Participants
The Multi-Ethnic Study of Atherosclerosis (MESA) recruited men and women ages 45-84 years without clinical cardiovascular disease.
Measurements
The MESA Lung Study measured spirometry following American Thoracic Society guidelines and urinary cotinine levels by immunoassay. Pipe-years and cigar-years were calculated as years from self-reported age of starting to quitting (or to current age among current users) × pipefuls or cigars per day.
Results
Of 3,528 participants, 8% reported pipe smoking (median 15 pipe-years), 11% reported cigar smoking (median 6 cigar-years), and 52% reported cigarette smoking (median 18 pack-years). Self-reported current pipe and cigar smokers had elevated urinary cotinine levels compared to never smokers. Pipe-years were associated with decrements in the forced expiratory volume in one second (FEV1) and cigar-years were associated with decrements in the FEV1 and the ratio of the FEV1 to the forced vital capacity. Participants who smoked pipes or cigars had an increased odds of airflow obstruction whether they had also smoked cigarettes (Odds ratio 3.43; 95% CI: 1.75, 6.71; P<0.001) or had never smoked cigarettes (Odds ratio 2.31; 95% CI: 1.04, 5.11; P=0.039) compared to participants with no smoking history.
Limitations
Cross-sectional design.
Conclusions
Pipe and cigar smoking increased urinary cotinine levels and was associated with decrements in lung function and increased odds of airflow obstruction, even among participants who never smoked cigarettes.
doi:10.1059/0003-4819-152-4-201002160-00004
PMCID: PMC2906916  PMID: 20157134
17.  What role may symptoms play in the diagnosis of airflow limitation? 
Background
Chronic obstructive pulmonary disease (COPD) is an under-diagnosed condition. General practitioners meet and examine the patients in early stages of the disease, and symptoms represent the starting point of the diagnostic process.
Aim
To evaluate the diagnostic value of respiratory symptoms in the diagnosis of airflow limitation.
Methods
Spirometry was performed in a cross-sectional population-based study of 3954 subjects 60 years and older (54.5% women), who also filled in a questionnaire on symptoms.
Results
The prevalence of any airflow limitation was 15.5% and 20.8%, in women and men, respectively, whereas the corresponding prevalence of severe airflow limitation (FEV1<50% predicted) was 3.4% and 4.9%. The positive predictive value of chronic cough with phlegm for any airflow limitation was 37.0% in women and 40.4% in men, and 17.3% and 14.2%, respectively, for severe airflow limitation. Wheezing was a symptom which persisted despite smoking cessation, whereas coughing was considerably less common in ex-smokers than in current smokers. Wheezing, dyspnoea on unhurried walking, dyspnoea on quick walking, and coughing with phlegm were independent predictors of any airflow limitation, OR 1.5, 1.8, 1.4, and 1.6 respectively. (The ORs for severe airflow limitation were 2.4, 2.4, 2.4, and 1.6 respectively.) To be an ex-smoker (OR 2.4) or a current smoker (OR 5.8) was of greater importance. In never- and ex-smokers the chance of having airflow limitation was almost doubled when having two or more, compared with one, of the three symptoms: wheezing, dyspnoea, and coughing with phlegm. Ex-smokers reporting two symptoms had a similar risk of airflow limitation to current smokers not reporting any symptoms.
Conclusion
Respiratory symptoms are valuable predictors of airflow limitation and should be emphasized when selecting patients for spirometry.
doi:10.1080/02813430802028938
PMCID: PMC3406655  PMID: 18570007
Airflow limitation; COPD; elderly; family practice; spirometry; symptoms
18.  Alterations of the Arginine Metabolome in Asthma 
Rationale: As the sole nitrogen donor in nitric oxide (NO) synthesis and key intermediate in the urea cycle, arginine and its metabolic pathways are integrally linked to cellular respiration, metabolism, and inflammation.
Objectives: We hypothesized that arginine (Arg) bioavailability would be associated with airflow abnormalities and inflammation in subjects with asthma, and would be informative for asthma severity.
Methods: Arg bioavailability was assessed in subjects with severe and nonsevere asthma and healthy control subjects by determination of plasma Arg relative to its metabolic products, ornithine and citrulline, and relative to methylarginine inhibitors of NO synthases, and by serum arginase activity. Inflammatory parameters, including fraction of exhaled NO (FeNO), IgE, skin test positivity to allergens, bronchoalveolar lavage, and blood eosinophils, were also evaluated.
Measurements and Main Results: Subjects with asthma had greater Arg bioavailability, but also increased Arg catabolism compared with healthy control subjects, as evidenced by higher levels of FeNO and serum arginase activity. However, Arg bioavailability was positively associated with FeNO only in healthy control subjects; Arg bioavailability was unrelated to FeNO or other inflammatory parameters in severe or nonsevere asthma. Inflammatory parameters were related to airflow obstruction and reactivity in nonsevere asthma, but not in severe asthma. Conversely, Arg bioavailability was related to airflow obstruction in severe asthma, but not in nonsevere asthma. Modeling confirmed that measures of Arg bioavailabilty predict airflow obstruction only in severe asthma.
Conclusions: Unlike FeNO, Arg bioavailability is not a surrogate measure of inflammation; however, Arg bioavailability is strongly associated with airflow abnormalities in severe asthma.
doi:10.1164/rccm.200710-1542OC
PMCID: PMC2556449  PMID: 18635886
asthma; arginine; arginase; nitric oxide; methylarginine
19.  Prevalence of bronchial reactivity to inhaled methacholine in New Zealand children. 
Thorax  1986;41(4):283-289.
The prevalence of bronchial hyperreactivity to inhaled methacholine and of a clinical history of symptoms of asthma was determined in a birth cohort of 9 year old New Zealand children. A history of current or previous recurrent wheezing was obtained in 220 of 815 children. Of 800 who had spirometric tests, 27 (3.4%) had resting airflow obstruction (FEV1/FVC less than 75%). Methacholine challenge was undertaken without problem in 766 children, the abbreviated protocol being based on five breaths and four concentrations. A fall in FEV1 of more than 20% was observed in 176 children (23% of challenges, 22% of the full cohort) after inhalation of methacholine in concentrations of up to 25 mg/ml. The prevalence of bronchial reactivity in children with symptoms was related to the frequency of wheezing episodes in the last year, and the degree of reactivity to the interval since the last episode. Sixty four children (8.0%) with no history of wheeze or recurrent dry cough were, however, also responsive to methacholine 25 mg/ml or less, while 35% of children with current or previous wheezing did not respond to any dose of methacholine. Bronchial challenge by methacholine inhalation was not sufficiently sensitive or specific to be useful as a major criterion for the diagnosis of asthma in epidemiological studies. The occurrence of airway reactivity in children without symptoms of asthma, however, raises the possibility that adult onset asthma and the development of airways obstruction in some subjects with chronic bronchitis could have origins in childhood.
PMCID: PMC460311  PMID: 3738848
20.  Determinants of airflow obstruction in severe alpha‐1‐antitrypsin deficiency 
Thorax  2007;62(9):806-813.
Background
Severe α1‐antitrypsin (AAT) deficiency is an autosomal recessive genetic condition associated with an increased but variable risk for chronic obstructive pulmonary disease (COPD). A study was undertaken to assess the impact of chronic bronchitis, pneumonia, asthma and sex on the development of COPD in individuals with severe AAT deficiency.
Methods
The AAT Genetic Modifier Study is a multicentre family‐based cohort study designed to study the genetic and epidemiological determinants of COPD in AAT deficiency. 378 individuals (age range 33–80 years), confirmed to be homozygous for the SERPINA1 Z mutation, were included in the analyses. The primary outcomes of interest were a quantitative outcome, forced expiratory volume in 1 s (FEV1) percentage predicted, and a qualitative outcome, severe airflow obstruction (FEV1 <50% predicted).
Results
In multivariate analysis of the overall cohort, cigarette smoking, sex, asthma, chronic bronchitis and pneumonia were risk factors for reduced FEV1 percentage predicted and severe airflow obstruction (p<0.01). Index cases had lower FEV1 values, higher smoking histories and more reports of adult asthma, pneumonia and asthma before age 16 than non‐index cases (p<0.01). Men had lower pre‐ and post‐bronchodilator FEV1 percentage predicted than women (p<0.0001); the lowest FEV1 values were observed in men reporting a history of childhood asthma (26.9%). This trend for more severe obstruction in men remained when index and non‐index groups were examined separately, with men representing the majority of non‐index individuals with airflow obstruction (71%). Chronic bronchitis (OR 3.8, CI 1.8 to 12.0) and a physician's report of asthma (OR 4.2, CI 1.4 to 13.1) were predictors of severe airflow obstruction in multivariate analysis of non‐index men but not women.
Conclusion
In individuals with severe AAT deficiency, sex, asthma, chronic bronchitis and pneumonia are risk factors for severe COPD, in addition to cigarette smoking. These results suggest that, in subjects severely deficient in AAT, men, individuals with symptoms of chronic bronchitis and/or a past diagnosis of asthma or pneumonia may benefit from closer monitoring and potentially earlier treatment.
doi:10.1136/thx.2006.075846
PMCID: PMC2117297  PMID: 17389752
21.  Detection of airflow limitation using a handheld spirometer in a primary care setting 
Respirology (Carlton, Vic.)  2014;19(5):689-693.
Background and objective
Early diagnosis of chronic obstructive pulmonary disease (COPD) in primary care settings is difficult to achieve chiefly due to lack of availability of spirometry. This study estimated the prevalence of airflow limitation among chronic smokers using a handheld spirometer in this setting.
Methods
This is a cross-sectional study performed on consecutive patients who were ≥40 years old with ≥10 pack-years smoking history. Face-to-face interviews were carried out to obtain demographic data and relevant information. Handheld spirometry was performed according to a standard protocol using the COPd-6 device (Model 4000, Vitalograph, Ennis, Ireland) in addition to standard spirometry. Airflow limitation was defined as ratio of forced expiratory volume in 1 s (FEV1)/forced expiratory volume in 6 s <0.75 (COPd-6) or FEV1/forced vital capacity <0.7. Multiple logistic regression analyses were used to determine predictors of airflow limitation.
Results
A total of 416 patients were recruited with mean age of 53 years old. The prevalence of airflow limitation was 10.6% (n = 44) with COPd-6 versus 6% as gauged using standard spirometry. Risk factors for airflow limitation were age >65 years (odds ratio (OR) 3.732 95% confidence interval (CI): 1.100–1.280), a history of ‘bad health’ (OR 2.524, 95% CI: 1.037–6.142) and low to normal body mass index (OR 2.914, 95% CI: 1.191–7.190).
Conclusions
In a primary care setting, handheld spirometry (COPd-6) found a prevalence of airflow limitation of ∼10% in smokers. Patients were older, not overweight and had an ill-defined history of health problems.
SUMMARY AT A GLANCE
Prevalence of COPD is unknown in Malaysia. The prevalence of COPD using a handheld spirometer (COPd-6TM) was 10.6% versus 6% as gauged using standard spirometry. Predictors of COPD were older age, lower BMI and a history of ‘bad health’. Case-finding for COPD should be targeted in this special population.
doi:10.1111/resp.12291
PMCID: PMC4230390  PMID: 24708063
chronic obstructive pulmonary disease; Malaysia; prevalence; primary care; smoke
22.  Citric acid cough threshold and airway responsiveness in asthmatic patients and smokers with chronic airflow obstruction. 
Thorax  1991;46(9):638-642.
The relation between citric acid cough threshold and airway hyperresponsiveness was investigated in 11 non-smoking patients with allergic asthma (mean FEV1 94% predicted) and 25 non-atopic smokers with chronic airflow obstruction (mean FEV1 65% predicted). Cough threshold was determined on two occasions by administering doubling concentrations of citric acid. Seven of the 11 asthmatic subjects and 14 of 25 smokers with chronic airflow obstruction had a positive cough threshold on both test days. Cough threshold measurements were reproducible in both groups (standard deviation of duplicate measurements 1.2 doubling concentrations in asthma, 1.1 doubling concentrations in chronic airflow obstruction). Citric acid provocation did not cause bronchial obstruction in most patients, though four patients had a fall in FEV1 of more than 20% for a short time on one occasion only. No significant difference in cough threshold was found between the two patient groups despite differences in baseline FEV1 values. There was no significant correlation between cough threshold and the provocative concentration of histamine causing a 20% fall in FEV1 (PC20) histamine in either group. Thus sensory nerves can be activated with a tussive agent in patients with asthma and chronic airflow obstruction without causing bronchial smooth muscle contraction.
PMCID: PMC463351  PMID: 1948792
23.  Relationships among Smoking Habits, Airflow Limitations, and Metabolic Abnormalities in School Workers 
PLoS ONE  2013;8(11):e81145.
Background
Chronic obstructive pulmonary disease is caused mainly by habitual smoking and is common among elderly individuals. It involves not only airflow limitation but also metabolic disorders, leading to increased cardiovascular morbidity and mortality.
Objective
We evaluated relationships among smoking habits, airflow limitation, and metabolic abnormalities.
Methods
Between 2001 and 2008, 15,324 school workers (9700 males, 5624 females; age: ≥30 years) underwent medical checkups, including blood tests and spirometry. They also responded to a questionnaire on smoking habits and medical history.
Results
Airflow limitation was more prevalent in current smokers than in ex-smokers and never-smokers in men and women. The frequency of hypertriglyceridemia was higher in current smokers in all age groups, and those of low high-density-lipoprotein cholesterolemia and diabetes mellitus were higher in current smokers in age groups ≥ 40 s in men, but not in women. There were significant differences in the frequencies of metabolic abnormalities between subjects with airflow limitations and those without in women, but not in men. Smoking index was an independent factor associated with increased frequencies of hypertriglyceridemia (OR 1.015; 95% CI: 1.012–1.018; p<0.0001) and low high-density-lipoprotein cholesterolemia (1.013; 1.010–1.016; p<0.0001) in men. Length of smoking cessation was an independent factor associated with a decreased frequency of hypertriglyceridemia (0.984; 0.975–0.994; p = 0.007).
Conclusions
Habitual smoking causes high incidences of airflow limitation and metabolic abnormalities. Women, but not men, with airflow limitation had higher frequencies of metabolic abnormalities.
doi:10.1371/journal.pone.0081145
PMCID: PMC3843673  PMID: 24312268
24.  The Course of Persistent Airflow Limitation in Subjects with and without Asthma 
Respiratory medicine  2008;102(10):1473-1482.
Rationale
Most patients who develop persistent airflow limitation do so either as a manifestation of chronic obstructive pulmonary disease that is largely related to smoking or as a consequence of persistent asthma. We sought to compare the natural course of lung function associated with persistent airflow limitation in subjects with and without asthma from early to late adult life.
Methods
We studied 2552 participants aged 25 or more who had multiple questionnaire and lung function data from the long-term prospective population-based Tucson Epidemiological Study of Airway Obstructive Disease. Persistent airflow limitation was defined as FEV1/FVC ratio consistently < 70% in all completed surveys subsequent to the first survey with airflow limitation. Participants were divided into nine groups based on the combination of their physician-confirmed asthma status (never, onset ≤ 25 years, or onset > 25 years) and the presence of airflow limitation during the study follow-up (never, inconsistent, or persistent).
Results
Among subjects with an asthma onset ≤ 25 years, blood eosinophilia increased significantly the odds of developing persistent airflow limitation (adjOR: 3.7, 1.4–9.5), whereas cigarette smoking was the strongest risk factor for persistent airflow limitation among non-asthmatics and among subjects with asthma onset after age 25 years. Among subjects with persistent airflow limitation, the natural course of lung function differed between subjects with asthma onset ≤ 25 years and non-asthmatics, with the former having lower FEV1 levels at age 25 (predicted value for a 175-cm tall male of 3,400 versus 4,090 ml, respectively; p<0.001) and the latter having greater FEV1 loss between age 25 and 75 (1,590 versus 2,140 ml; p=0.003).
Conclusion
In subjects who have asthma onset before 25 years of age and persistent airflow limitation in adult life, the bulk of the FEV1 deficit is already established before age 25 years.
doi:10.1016/j.rmed.2008.04.011
PMCID: PMC2629140  PMID: 18684603
asthma; COPD; eosinophilia; airflow limitation
25.  Occupational Risk Factors for COPD Phenotypes in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study 
COPD  2014;11(4):368-380.
Introduction
The contribution of occupational exposure to the risk of chronic obstructive pulmonary disease COPD in population-based studies is of interest. We compared the performance of self-reported exposure to a newly developed JEM in exposure-response evaluation.
Methods
We used cross-sectional data from Multi-Ethnic Study of Atherosclerosis (MESA), a population-based sample of 45–84 year olds free of clinical cardiovascular disease at baseline. MESA ascertained the most recent job and employment, and the MESA Lung Study measured spirometry, and occupational exposures for 3686 participants. Associations between health outcomes (spirometry defined airflow limitation and Medical Research Council-defined chronic bronchitis) and occupational exposure [self-reported occupational exposure to vapor-gas, dust, or fumes (VGDF), severity of exposure, and a job-exposure matrix (JEM)-derived score] were evaluated using logistic regression models adjusted for non-occupational risk factors.
Results
The prevalence of airflow limitation was associated with self-reported exposure to vapor-gas (OR 2.6, 95%CI 1.1–2.3), severity of VGDF exposure (P-trend<0.01), and JEM dust exposure (OR 2.4, 95%CI 1.1–5.0), and with organic dust exposure in females; these associations were generally of greater magnitude among never smokers. The prevalence of chronic bronchitis and wheeze was associated with exposure to VGDF. The association between airflow limitation and the combined effect of smoking and VGDF exposure showed an increasing trend. Self-reported vapor-gas, dust, fumes, years and severity of exposure were associated with increased prevalence of chronic bronchitis and wheeze (P<0.001).
Conclusions
Airflow limitation was associated with self-reported VGDF exposure, its severity, and JEM-ascertained dust exposure in smokers and never-smokers in this multiethnic study.
doi:10.3109/15412555.2013.813448
PMCID: PMC4096066  PMID: 24568208
Spirometry; airflow obstruction; job exposure matrix; gas; dust; fumes

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