IN SMOKING PREVALENCE & COPD IN NEVER-SMOKERS
VER THE LAST
50
YEARS TOBACCO consumption slowly decreased.Health promotion campaigns, successive ban on advertisement, then smoking in public places and societal views of smoking led to a paradigm change from smoking as a positively held personal choice toward a costly dependence affecting not only smoker’s health but also those exposed to second hand smoke.
Few data are available on smoking prevalence for Switzerland before the first Swiss Health Survey in 1992[63, 64]. In the nineties, Swiss residents reported more frequently to be smoker compared to other 16 countries from the OECD (Organization for economic co-operation &
development). However, data from SAPALDIA suggest that amount of cigarettes equivalents (Pack years) are lower compared to others. Nevertheless, Switzerland’s tobacco policy control lags behind most westernized countries. As a result, smoking prevalence remained high. A recent analysed by Marques-Vidal showed however a favourable trend, which was more apparent for men than for women[65]. (See figures on pages 53 & 54)
Figure: Percentage of men and women who reported that they smoke daily (2004) source: OECD report[66]. Switzerland prevalence appears close to OECD average.
O
Figure: Trends 1960-2007 in irevalence of smoking in Switzerland, USA and 16 OECD countries (Compiled from different sources: Center for Disease Control (USA), Swiss health study 1992 - 2007, OECD report)
15 20 25 30 35 40 45 50
1960 1970 1980 1990 2000 2007
Current smokers (% of adult population)
Switzerland Men Switzerland Women USA All OECD 16 countries Men OECD 16 countries Women
I
MPORTANCE OF NON-
SMOKING RELATEDCOPD
This favourable trend is intrinsically associated with a trend toward higher proportion of never-smokers among patients with COPD. Selecting 10 recent and large studies reporting the proportion of never-smokers among COPD subjects, we found that the proportion of never smokers in subjects with AO was 20% for studies designed between1980-1990 and increase to 30% for the decade 2000-2010. The table on page 56 details individual characteristics of these studies.
Graphically examining the relation between time (year) and proportion of never-smokers, the trend was apparent (Figure on page 55).
Figure: Ten-year trend in proportion of subjects with COPD who never smoked (2000-2010) in ten studies.
Pena 2000 Birring 2002 Trupin 2003 Behrendt 2005 Celli 2005 Menezes 2005 Kim 2005 Lamprecht 2008 Zhou 2009 Bridevaux 2010
.18 .2 .22 .24 .26 .28 .3 .32 .34 .36 .38 .4
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Year
Italy banned smoking in public spaces in 2004, (Personal photo, Aosta, Italy, 2005)
Table: Proportion of non-smokers in COPD patients
Author, journal Year
Proportion of non-smokers
Country Design Identified risk factors Comments
Whittemore,
Am J Public Health 1995 NA USA NHANES I & II (1971 -1980) , population study, 12980 non smokers
Ageing, female sex, low income, Caucasian,
Physician diagnosed COPD. COPD prevalence 3.8%M and 5.6%W
Pena,
Chest[67] 2000 23.4% Spain IBERPOC, Population study, cross sectionnal,
4035 subjects Geographic variations Spirometry with ERS COPD criterion to define COPD
Birring,
AJRCCM[68] 2002 22.9% UK
Case series of 25 non smokers with COPD compared with 117 smokers with COPD. Study reports 5.7% of non-smoker with COPD
Sputum eosipnophilia or neutrophilia, female sex, auto-immune pattern (32%)
Spirometry confirmed. Chest CT non specific.
Trupin,
Eur Resp J[69] 2003 19 % USA Population study, 2061 subjects >55yo,
Occupational exposures to vapour gas dust or fumes (OR 2.0 [1.6 - 2.5])
Physician diagnosed COPD, underestimation likely
Behrendt,
Chest[52] 2005 24.9 % USA NHANES III, Population study, cross sectionnal,
(1988-1994), 13995 subjects Asthma, ageing, male sex No data on genetics, ETS, air pollution, BHR, spirometry with modified GOLD criterion, stage 2 Celli,
Am J of Med[51] 2005 23.0% USA NHANES III, Population study, cross sectionnal, (1988-1994), 13332 subjects
Ageing, male sex, low BMI, history of allergy
Modified GOLD criterion, including stage 1 COPD. COPD prevalence in non-smokers 9.1%
Menezes,
Lancet[26] 2005 32.0%* South
America
PLATINO, Population study, cross sectionnal, 5571 subjects
No specific analysis of COPD in non smokers
Spirometry with GOLD criterion, important between-cities variations: 44.5% in Mexico, 23.2%
in Caracas. Lowest overall COPD prevalence and smoking prevalence (45.6%) in Mexico
Lindberg,
Respiration[70] 2005 24.6 % Sweden OLIN population study 645 subjects No specific analysis Prevalence of COPD in never smokers varied from 3.4% (BTS definition) to 24.5% (ATS definition) Kim,
AJRCCM[71] 2005 32.1% South Korea Korean NHANES II, population study, cross-sectionnal, 9243 subjects
No specific analysis of COPD in non smokers. Authors suggest asthma and biomass exposure as predictors
Spirometry with modified GOLD criterion. 88% of men with COPD smoked; 90% of women with COPD neversmoked
Lamprecht,
Respir Med[41] 2008 27.7% Austria BOLD, population study, cross sectionnal, Ageing, female sex, asthma, organic dust in the workplace
GOLD criterion stage 2+ (COPD stage 1+
prevalence in never smokers: 18.2%; stage 2+:
5.5%)
Zhou,
Eur Resp J[54] 2009 38.6% China CESCOPD, Population study, 13495 subjects, female 88.7%.
Male sex, ageing, indoor air pollution, familial history of respiratory disease, chronic cough childhood, ETS (p=0.039)
GOLD criterion, COPD prevalence in non-smokers 5.2%
Bridevaux,
2010 29.3% Switzerland SAPALDIA, Population study, 6126 subjects Male sex, asthma, BHR Lower limit of normal of FEV1/FVC ratio & stage
Figure: Relation between country-specific smoking prevalence and proportion of subjects with COPD who never smoked (2000-2010) in nine studies. Countries with lower prevalence of smoking had higher prevalence of never smokers among subjects with COPD
Proportion of subjects with COPD who never smoked (%)
35 40 45 50 55 60 65
Country smoking prevalence (%)
In 2010, the ATS published an extensive statement on the factors, beyond smoking, causing COPD. The ad hoc committee calculated Population-Attributable Risk (PAR) for smoking, and non-smoking risk factors. This findings are summarized in the table on page 58 (adapted from Eisner et al)[73]. PAR not attributable to smoking were generally higher for women, older population and those living in developing countries. This can be explained by lower smoking prevalence among women in developing countries and higher exposure to biomass smoke.
Table: Population-attributable risk (PAR) for COPD related mortality due to smoking (adapted from Eisner et al, AJRCCM 2010)
Source, year Year Setting Sex Age group PAR
Decreasing smoking prevalence, ageing populations allow other risk factors for COPD to emerge. In the section below, these novel risk factors are discussed.
Environmental tobacco smoke
ETS contains respiratory irritants which may lead to airways inflammation and lung function decline [75, 76]. A large body of studies support an association between ETS, in particular during infancy, and asthma or lung function at adulthood. Smoking ban implementation also led to lung function improvement in bar workers who were never smokers. A SAPALDIA study found a strong association between ETS and Health-related Quality of Life (HRQoL) among never smokers [50]. In the same study we found that those ETS exposed also reported more health care use compared to the non-exposed. We found an exposure/effect relationship.
However, ETS as a causal factor for COPD received little attention until recently.
In industrialized countries, one population study of 2113 adults in USA found that home and work ETS exposure was associated with physician-diagnosed COPD after adjustment for smoking history (OR 1.55 [CI95% 1.09 to 2.21][73, 77]. In NHANES, the association was not found[51].
In developing countries, two different cohort studies on Chinese subjects who never smoked found an association (OR 1.31 [CI95% 1.06 – 1.61]) (OR 1.48 [CI95% 1.18 – 1.85]) [54] [53]
ETS may also enhance the risk of COPD in smokers. For example, in SAPALDIA, we found an association between ETS and risk of COPD in smokers (OR 1.87[CI95% 1.05 – 3.3]) but not in never smokers (OR 1.54 [CI95% 0.44 – 3.3])[72]. The meaning of the association is to be interpreted with caution. Residual confounding (lower socio-economical status of smokers) and difficult assessment of true exposure to ETS may partly explain the association.
In summary, the ATS expert panel found a positive association between ETS and COPD (OR 1.55 [CI95% 1.40 1.74]). The causal association is possible but currently strong evidences are lacking to proof that ETS cause COPD. Interestingly the association was mainly found in developing countries in not developed ones.
Environmental tobacco smoke control campaign “secondhandsmokesyou.com”, Seattle 2002
Asthma
Pulmonary physicians frequently face patients with difficult asthma. These patients are frequently older with a long history of respiratory complaints, without atopy or exposure to smoking. The pulmonary function test exhibits a mild or moderate obstruction which is not reversed by bronchodilators. Corticoid therapy trials are deceptive. Many of these features are found in COPD which is known to be disease with few if any response to corticosteroid therapy
Such a phenotype, namely irreversible asthma, has been described in several case series[78, 79]. Some of the characteristics of these asthma patients are found in COPD patients. Cases series helped to identify the following risk factors associated either with irreversible asthma or accelerated decline in FEV1. Some of these characteristics are detailed in the table on page 61.
Table: Risk factors associated with irreversible asthma or accelerated lung function decline
Risk factors Reference
Long duration of asthma [78-80]
Old age [78-80]
Abnormal chest CT scan [79, 81]
Emphysema [79, 81]
Bronchial wall thickening [79, 81]
Low baseline lung function
Bronchial hyper-responsivness [55]
Mucus production
Male sex [15]
Atopy Association
unclear
The Tucson cohort study brought evidence that asthma is a risk factor for COPD
development. The cohort followed 3099 adults with questionnaires and serial spirometry over 20 years. Subjects were classified in controls, active asthma (reporting current asthma, n=192) or inactive asthma (n=156). Those with active asthma at cohort inception were more than 10 times more likely to develop COPD (Hazard Ratio 12.5 [CI95% 6.83 - 22.8][56].
In SAPALDIA, our study on the prevalence of airflow obstruction found that asthma, as reported in 1991, was a strong risk factor for having airflow obstruction at follow-up in never smokers (OR 3.25 [CI95% 1.45 7.31]. In line with previous study, atopic status was not associated with COPD. We also report a similar impact on HRQoL and respiratory symptoms in subjects with or without smoking history (henceforth more likely to report asthma). This suggests that the clinical consequences of airflow obstruction are similar in patients with typical smoking related COPD and those with long duration, atypical asthma.
In summary, the association between long duration asthma and COPD is strong. A common pathological pathway may lead to similar radiological pattern in clinical series of asthma and COPD patients. However, the phenotypes of subjects with asthma evolving to COPD and
Bronchial hyper-responsiveness
Broncho-constriction induced by the non specific agent methacholine, administered at increasing dose, is called bronchial hyper-responsiveness (BHR) (defined by a 20% or more FEV1 reduction of the baseline value). The current opinion is that BHR is a marker of smooth muscle dysfunction induced by bronchial inflammation. BHR is a sensitive but unspecific hallmark of active asthma and is found in 10 to 20% of the general population. Women, healthy smokers, subjects with low lung function are more likely to have BHR. Among those with BHR, 20 to 60% are asymptomatic.
The long-term significance of asymptomatic (or ―silent‖) BHR has been studied by Brutsche et al using the SAPALDIA cohort [55]. Notably, the incidence of COPD, as defined with the GOLD criteria, was measured in asymptomatic subjects with or without BHR at baseline. Of those without BHR, 14.3% were diagnosed with COPD at follow up vs 37.9% for those with baseline BHR. Adjusted for factors commonly associated with BHR, risk of COPD was increased by 4.5 times (OR 4.5 [CI95% 3.3 6.9]) [55]. This study confirms the role of BHR in the pathogenesis of COPD as defined with the GOLD criteria.
Using a more specific definition of COPD (namely stage II COPD with lower limit of normal cut off for FEV1/FVC ratio), we found a stronger association between SAPALDIA I BHR and development of COPD[72]. Never smokers with BHR at baseline had a 8-fold increase in COPD stage II risk 11 years later (OR 8.2 [CI95% 4.2 16.2]). In smoker the risk was even higher (OR9.6 [CI95% 6.2 15.0]). Taken together, these findings support a role for BHR in the pathogenesis of COPD.
Air pollution
Air pollution is a mixture of fine particles (particulate matter 10 micrometer (PM)) of various sizes, vapors, gazes that originates from different sources such as traffic, industry, heating, or even forest fire. In Switzerland, traffic related pollution is the main source of PM and is heterogeneously distributed. (See figure on page 63)
Figure: Air pollution in Switzerland (Source SAPALDIA)
Air pollution cannot be individually avoided, given it is ubiquitous. Since COPD prevalence is increasing while smoking prevalence is decreasing and global urbanization progress, the causative role of air pollution in the pathogenesis of COPD need to be extensively studied [46].
Air pollution & lung function
The role of air pollution on pulmonary function is well documented. Long term exposure to air pollution during childhood caused detrimental effect on lung function growth. Increasing air pollution levels, approximated by distance to main roads, and measured during the first years of life was associated with lower FEV1 achieved at age 18 [83]. A longitudinal study from SAPALDIA (n=4742) showed that better air quality (reduction in PM10 level) in Switzerland over 11 years was associated with a slower lung function decline. This study confirmed that the clean air policies implemented in the 80ies and 90ies improved air quality and thus contributed to better global respiratory health [49].
Air pollution & established COPD
In subjects with established COPD, outdoor air pollution peaks clearly contribute to COPD exacerbations, as measured with respiratory mortality or emergency care use [84, 85].
Also, overall cardiopulmonary mortality is increased by long-term exposure to air pollutants [86]. A Norwegian study showed that persons with COPD were more susceptible to die as a result of air pollution exposure [87].
However, the role of outdoor air pollution as a causal factor of COPD is debated.
Misclassification of exposure due to coarse measurements (central site only) led associations toward the null for many years. Modern methodological approaches allowing individual assessment of outdoor air pollution exposure have been developed. Land use regression models, which integrate individual data such as home address, central site, on site air pollutant measurements, local traffic density & distance to main road provide a much reliable exposure to air pollution, thus limiting misclassification of exposure. As a consequence, the role of long-term exposure to air pollutants as a causal factor for COPD may be revealed.
Recent studies in the field are discussed below.
Outdoor air pollution
In 2003, Karakatsani et al designed a case-control study in Athens (Greece). They enrolled 84 cases with COPD (physican diagnosed COPD cases) and 168 controls. Exposure to black smoke and Nitrogen dioxide (NO2) over 20 and 5 years were measured. The highest exposure group (5 years) had a two-fold increase in risk of having COPD compared to the lowest exposed (OR 2.01 [1.05 – 3.86]. Long-term exposure (20 years) was not associated with COPD [88].
In 2005, the German SALIA women’s cohort (Study on the influence of Air pollution on Lung function, Inflammation and Aging), analyzed the COPD prevalence (GOLD stage 1 disease) in relation with long-term exposure to PM10 and NO2. Schikowsky reported a higher risk of COPD for increasing exposure to PM10 (OR 1.33 [CI95% 1.03 1.72 per 7 ug/m3 increase) and NO2 (OR 1.39 [CI95% 1.20 1.63 per 16 ug/m3 increase)[89]. It should be noted
Figure: NOx levels in Europe. (Source IUP Heidelberg, Institut für Umweltphysik )
In 2009, a Swedish study, enrolling 9319 adults, found an association between distance to main road (>10 cars/min) and asthma (OR 1.40, [CI95%1.04-1.89]) or COPD (OR 1.64 [CI95% 1.11 2.40]). Interestingly, the association was evident despite low air pollution level in South Sweden [90].
In 2011, the first longitudinal study on risk of COPD and air pollution was published [91]..
The Danish study followed 57’053 adults for 35 years. First admission for COPD and 35-year NO2 exposure were recorded. Incidence of COPD increased with NO2 exposure (HR 1.08 [CI95% 1.02 1.14]). The authors also found a stronger effect of air pollution on subjects with asthma, diabetes and obesity. These findings corroborate other SAPALDIA studies[47].
First, we showed that asthma is a strong risk for COPD [72].
Second, we found in another SAPALDIA study that adult-onset asthma was associated with long-term exposure to PM10 [47]. These results also highlight the role of PM to potentially cause obesity or diabetes , through inflammation from adipose tissue triggered by fine
In summary, studies accumulate to bring evidence of a causal relationship between long-term exposure to air pollution and COPD. However, longitudinal studies are lacking and other cross-sectional studies did not find any association [93].
Forest fires dramatically increases air pollution in rural areas (Forest fire in Oregon, 2003)
Indoor air pollution
Similar mechanisms explaining the pro-inflammatory effect of smoking to cause COPD apply to indoor air pollution. Two separate meta-analyses confirmed that exposure to indoor air pollution is associated with COPD.
The meta-analyse by Hu selected 15 studies and found an increase in the risk of COPD (Global OR 2.44 [1.90 -3.33]) associated with biomass smoke [94].
Given that more than half of the human population use wood stove for heating and cooking, risk of COPD caused by biomass smoke exposure might be the first cause of COPD globally.
(See figure on page 67)
Figure: Proportion of household which use biomass. Source Lancet
Woman burning biomass to prepare food
Genetic factors
Alpha1-antitrypsine deficiency (PI Z) is the only genetic risk factors associated with COPD or rapidly declining lung function in smokers but also possibly in never-smokers [96, 97]. Four percent of subjects of Europeans descent carry the Pi Z allele and 1/5000 carry the Pi ZZ or PI Z null forms which are associated with COPD. Thus, among COPD patients, only 1 or 2 percent have the Alpha1-antitrypsine deficiency. Also, emphysema related to the alpha1-deficiency is multifactorial needing exposure to environmental factors (eg smoking) to develop. In SAPALDIA, we found that the gene variant SERPINA1 MS and MZ, resulting in intermediate deficiency in alpha1 antitrypsine (heterozygote subjects with only one Z allele deficiency) may already be sufficient to accelerate lung function decline in population subgroups characterized by elevated levels of low grade inflammation and oxidative stress, such as obese patients (Thun et al, unpublished results).
Genome-wide associations study (GWAS) provided several single nucleotide polymorphism (SNP) variant associated with lung function development. A systematic review of more than 20’000 subjects in Europe found eight loci associated with FEV1/FVC ratio: HHIP (hedgehog interacting protein), GPR126 (G-Protein-coupled receptor), ADAM19 (disintegrin and
Metalloprotease), AGER-PPT2 (immunoglobulin superfamily of cell surface receptors), FAM13A, PTCH1, PID1 and HTR4 (coding for hydroxytryptamine (serotonin) receptors) and one loci associated with FEV1 (INTS12-GSTCD-NPNT (glutathione S-transferase,
C-terminal domain) [98].
Limitations of GWAS deserve attention:
a) Up to now, the biological link between the pathogenesis of COPD and most SNP variants is hypothetical and need to be established.
b) To be true, GWAS need to be validated in different population, which is not the rule.
Extremely low P values as presented in GWAS do not offer absolute protection against selection bias [99].
c) Clinical applications of SNP study are to be developed. Genetic screening for disease risk begins to be commercially offered. However, at the present time, a positive genetic test does not add any information beyond already known risk factors (such as history of smoking, asthma or noxious exposure for COPD) [100]. Large-scale genetic testing is costly and useless, since no preventive treatment or general recommendation beyond noxious exposure avoidance can be offered.
Infections
An association between lower respiratory tract infections and adult lung function is well documented. Barker reported that bronchitis, pneumonia, or whooping cough in infancy further reduced adult lung function by 220 ml (CI95% 2 to 420) [101]. Johnston found that childhood pneumonia is associated with reduced ventilatory function in adults, independently of wheezing [102]. Recently, a study from the European Community Respiratory Health Survey confirmed the association. FEV1 at adult age was reduced by 70.1 ml (117.1 – 23.2) for those who reported a severe childhood infection [103]. However, in the same study, the
(GOLD stage II criteria). It was only when other early life risk factors were summed that the risk of COPD increased. The table below, extracted from Svanes’ article displays the findings.
Table Association of COPD with childhood disadvantage factors (adapted from Svanes) Men n=8201 Women n=8633 Severe respiratory infection before 5 years 1.34 (0.77 to 2.35) 0.69 (0.31 to 1.53) Number of childhood factors 0 (reference)
1 1.71 (1.10 to 2.64) 1.62 (1.01 to 2.60)
2 5.23 (3.14 to 8.73) 2.41 (1.26 to 4.61)
3 6.32 (2.35 to 16.98) 7.16 (2.75 to 18.64) Childhood factors: Maternal asthma or paternal asthma or childhood asthma or severe
infection before 5 years or maternal smoking
In summary, childhood infection may play a role as a causal factor for COPD, in particular if interaction with other factors, mostly related to lower socio-economical status, are involved.
Viral infections
Viral infections are clearly associated with COPD exacerbations. Viruses were identified in 20%- 50% of COPD exacerbations depending on the laboratory method used. Reverse Transcription Polymerase Chain reaction (PCR) are currently the most sensitive technique [104]. A cohort of 86 patients admitted at the University of Geneva Hospitals and screened
Viral infections are clearly associated with COPD exacerbations. Viruses were identified in 20%- 50% of COPD exacerbations depending on the laboratory method used. Reverse Transcription Polymerase Chain reaction (PCR) are currently the most sensitive technique [104]. A cohort of 86 patients admitted at the University of Geneva Hospitals and screened