INT J TUBERC LUNG DIS 18(7):870–875 Q 2014 The Union http://dx.doi.org/10.5588/ijtld.13.0652
Incidence of chronic bronchitis: a prospective study in a large general population † E. Andersson* ´ M. Holm,* K. Toren,*
*Department of Occupational and Environmental Medicine, Sahlgrenska University Hospital, Goteborg, ¨ Sweden; † Section of Occupational Medicine, Respiratory Diseases and Toxicology, University of Perugia, Perugia, Italy SUMMARY
A county in western Sweden. To prospectively investigate the incidence rate of chronic bronchitis (CB) in relation to smoking, age, sex, atopy and asthma in a large sample of the general population. D E S I G N : Subjects from a county in western Sweden born between 1943 and 1973, who had participated in our previous study in 1993, were mailed a new questionnaire in 2003. Altogether 11 463 (72%) answered the questionnaire, which comprised items about smoking, atopy, respiratory symptoms and age at onset of CB symptoms. CB was defined as chronic productive cough for at least 3 months per year for 2 consecutive years.
There were 98 new cases of CB during 1993– 2003 in the study population aged 30-60 years at followup. The incidence rate was 0.9/1000 person-years (py); there was no significant difference between women and men or different age groups. However, CB incidence was higher in women in relation to smoking (incidence rate ratio 3.6, 95%CI 1.9–7.3) and in those with ever asthma (hazard ratio 5.6, 95%CI 3.5–9.0). C O N C L U S I O N : This prospective general populationbased study shows an incidence rate of CB of 0.9/1000 py. Smoking and asthma were both associated with an increased risk of CB. K E Y W O R D S : chronic bronchitis; epidemiology; prospective; general population
AS REPORTED in a systematic review with metaanalysis, chronic bronchitis (CB) is a common disease with a calculated pooled global prevalence of 6.4%.1 CB prevalence is higher in middle-aged and elderly individuals, which, it has been suggested, may reflect a cohort effect rather than an effect of ageing.2 Another recent systematic review confirms that there is a close relation between CB and smoking.3 In addition, an association between CB and workrelated exposures to gas, dust and fumes,4-6 and, more specifically, welding fumes,7,8 has been shown. Finally, self-reported frequent chest infections in childhood have also been shown to presage CB.9 Historically, there have been several definitions of CB, and the condition has been closely associated with chronic obstructive pulmonary disease (COPD). Some studies have reported that the presence of chronic mucus production from the airways is not associated with the decline in forced expiratory volume in 1 second (FEV1) seen in COPD,10,11 while other studies have reported the opposite.12-14 It has been suggested that CB does not increase the risk of initial excess decline in FEV1 but exacerbates the process once it has started.2,15 Today, CB is usually
defined by the internationally accepted diagnostic criterion of a chronic productive cough for at least 3 months per year for 2 consecutive years,16,17 and it has been recommended that the term CB should be used only to indicate bronchial hypersecretion and never to denote associated airflow obstruction.18 It is important to study CB, as some studies have reported increased overall mortality even in subjects without reduced lung function.9,14,19,20 CB prevalence has been investigated by several groups, but few prospective studies have examined CB incidence in general populations.14,21-24 In addition, the definition of CB varies between these incidence studies; only Baik et al. have presented incidence rates for CB.24 The aim of the present prospective study was to investigate the incidence rate of CB in relation to smoking, age, sex, atopy and asthma in a large sample of the general population.
SETTING:
OBJECTIVE:
R E S U LT S :
STUDY POPULATION AND METHODS A random sample of 20 000 individuals in a county in western Sweden, born between 1943 and 1973, were sent a questionnaire in 1993. The questionnaire,
Correspondence to: Mathias Holm, Department of Occupational and Environmental Medicine, Box 414, SE 405 30 Goteborg, Sweden. Tel: (þ46) 317 866 279. Fax: (þ46) 3140 9728. e-mail: [email protected] ¨ Article submitted 4 September 2013. Final version accepted 15 March 2014.
Incidence of chronic bronchitis
which comprised items about airway symptoms and smoking, was answered by 15 813 subjects.25 At follow-up in 2003, the subjects were mailed a new questionnaire and 11 463 (72%) answered the questionnaire. However, 52 could not be linked to the first questionnaire and 4 had unreasonable smoking cessation data, leaving 11 407. The followup questionnaire contained new questions as well as questions identical to those in the baseline questionnaire. The internationally accepted diagnostic criterion, chronic productive cough for at least 3 months per year for 2 consecutive years, was used to define CB.16,17 CB was diagnosed in individuals who answered positively to all three of the following questions, which were included in both the baseline questionnaire and the follow-up questionnaire: ‘Have you, since the age of 15, suffered from long-standing cough with sputum?’, ‘If yes, has any period lasted for at least 3 months?’ and ‘If yes, have you had such periods for at least 2 consecutive years?’ In addition, the 2003 questionnaire also asked, ‘If yes, how old were you when these problems started?’ Atopy was defined as a positive answer to the question ‘Do you have, or have you ever had, hay fever?’ and/or ‘Do you have, or have you had, atopic dermatitis?’ Asthma was defined as an affirmative answer to the question ‘Have you been diagnosed as having asthma by a physician?’26 Smoking status was checked both at baseline and at follow-up, and was categorised as ‘never smoking’, ‘ex-smoking’ and ‘current smoking’. Year of starting to smoke and year of quitting smoking were also asked for, allowing us to classify every year into one of the smoking categories and thus calculate person-years (py). The SAS statistical package, version 9.2 (Statistical Analysis Software Institute, Cary, NC, USA), was used for most of the analyses. STATA (Stata Corp, College Station, TX, USA) was used for the incidence analyses. The incidence rate of CB (number of new cases/1000 py) with 95% confidence intervals (CIs) was calculated for the period 1993–2003. This was based on reported year of onset (‘How old were you when these symptoms started?’), with 2 years added to fulfil the diagnostic criterion.16,17 Subjects who met the diagnostic criterion for CB at baseline (n ¼ 168), or who reported year of onset before 1991 at Table 1
follow-up (n ¼ 73) or reported no year of onset (n ¼ 18) were excluded from the analyses. Subjects ceased to contribute py when they were diagnosed with CB. The py were divided into smoking, ex-smoking and non-smoking years. Incidence rate ratios with 95%CIs were calculated, comparing smoking py with non-smoking py. Cox regression analyses (PROC PHREG; Statistical Analysis Software Institute) were performed, with incident CB as an event and py under observation as the dependent variable. Hazard ratios (HRs) were calculated for the explanatory variables sex, atopy, asthma and age group (20– 30, 31–40 and 41–50 years) included simultaneously in the model for smoking, ex-smoking and nonsmoking years, respectively. When applying a model with all subjects, current smoking was included. The population attributable fraction of CB due to different risk factors was calculated using the formula: [(RR1)/RR*(exposed cases/cases)] (RR ¼ relative risk). The study was approved by the Ethics Committee ¨ 192-03). of Goteberg, Sweden (O ¨
RESULTS Among those who answered both questionnaires, CB prevalence was 1.5% in 1993 and 2.1% in 2003. After exclusion of individuals with CB at baseline and of those with no reported year of onset, 11 148 remained, representing a total of 109 410 py. The demographic characteristics for these subjects are shown in Table 1. There were 98 new CB cases during 1993–2003; the cumulative incidence for CB was 0.9% in the study population aged 30–60 years at follow-up. Around 30% of new CB cases also reported newonset (1993–2003) physician-diagnosed asthma. The crude incidence rate was 0.9/1000 py (95%CI 0.7– 1.1: 1.0/1000 py, 95%CI 0.7–1.3 in women and 0.8/ 1000 py, 95%CI 0.6-1.1 in men). Those individuals reporting atopy at baseline had an incidence rate of 1.2/1000 py (95%CI 0.8–1.7). There were only three new CB cases among those reporting asthma at baseline. Smokers had an incidence rate of 1.5/1000 py (95%CI 1.0–2.0). Table 2 shows incidence rates and RRs of CB by sex, atopy, age and asthma in the
Demographic characteristics of the study population at baseline by smoking groups
All Female subjects Subjects with atopy Subjects with asthma Age, years, mean 6 SD
Smokers n (%)
Ex-smokers n (%)
Never smokers n (%)
All* n (%)
3100 (27.8)† 1811 (58.4) 513 (16.6) 115 (3.7) 37.0 6 8.7
2238 (20.1)† 1127 (50.4) 480 (21.5) 102 (4.6) 39.7 6 7.5
5342 (47.9)† 2748 (51.4 ) 1261 (23.6) 199 (3.7) 34.3 6 9.1
11 148 (100)† 5918 (53.1) 2350 (21.1) 438 (3.9) 36.1 6 8.9
* Includes also those with missing smoking data. † Percentage of all individuals in the study. SD ¼ standard deviation.
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Table 2 Incidence rates (cases/1000 py) and relative risk of chronic bronchitis in relation to sex, atopy, age and asthma by smoking exposure Smoking years Incidence rate (95%CI) All Women Men Atopic* Non-atopic* 20–30 years* 31–40 years* 41–50 years* Asthma* Asthma 1993 or 2003
1.5 1.8 0.9 2.3 1.3 1.1 1.6 1.6 1.8 5.7
(1.0–2.0) (1.3–2.6) (0.4–1.6) (1.1–4.0) (0.9–1.8) (0.5–2.0) (0.9–2.7) (0.9–2.5) (0.2–6.3) (3.1–9.6)
Ex-smoking years Incidence rate (95%CI) 0.9 0.8 0.9 1.2 0.7 1.5 0.9 0.6 0.8 3.9
Never-smoking years Incidence rate (95%CI)
(0.6–1.3) (0.4–1.5) (0.5–1.6) (0.5–2.5) (0.4–1.2) (0.6–3.0) (0.4–1.7) (0.3–1.2) (0.02–4.7) (1.8–7.5)
Incidence rate ratio (smoking/never smoking years) Incidence rate (95%CI)
0.6 0.5 0.7 0.7 0.6 0.5 0.7 0.7
(0.4–0.9) (0.3–0.9) (0.4–1.1) (0.3–1.4) (0.4–0.9) (0.2–0.9) (0.4–1.3) (0.3–1.2) NA 1.9 (0.8–3.9)
2.4 3.6 1.2 3.1 2.3 2.3 2.3 2.3
(1.5–3.9) (1.9–7.3) (0.5–2.8) (1.2–8.6) (1.3–4.2) (0.8–6.3) (0.99–5.5) (1.03–5.4) NA 3.0 (1.1–8.9)
* At baseline. py ¼ person-years; RR ¼ relative risk; CI ¼ confidence interval; NA ¼ not applicable.
different smoking groups. Smoking seems to have increased the risk for incident CB in all groups but men (Table 2). If those who met the diagnostic criterion for CB in 2003 (but not in 1993) and reported no year of onset (n ¼ 18) or year of onset before 1993 (n ¼ 73) were included, the crude incidence rate was 1.7/1000 py (1998 was used as year of onset in this calculation, as it represented the midpoint in the 1993–2003 follow-up period). The relative importance of the studied variables associated with CB incidence did not substantially change when these individuals were included in the analyses. The Cox regression model, with mutual adjustments for all predictors, showed an increased RR for CB among current smokers and among subjects with asthma compared with those without asthma (Table 3). Among atopic subjects with incident CB, around 50% also had physician-diagnosed asthma (not shown). If ‘asthma 1993 or 2003’ was excluded from the analysis, atopy at baseline was associated with an increased risk of CB (HR 1.6, 95%CI 1.0–2.5). There was no significant difference between women and men, and the same was true when different age groups were compared (Table 3). The results concerning sex, atopy, age and asthma remained similar when a model including different smoking groups was used, except that female smokers seemed to have a non-significantly increased risk of incident CB compared with male smokers (Table 3). However,
men who were smokers at baseline were found to report ever having had symptoms of CB (in the 1993 and/or 2003 questionnaire) more often than men who were never-smokers (odds ratio [OR] 1.4, 95%CI 1.0–2.1). Male smokers were in general older than female smokers (mean age 37.9 vs. 36.4 years, P , 0.0001), and there tended to be more ex-smokers among men aged 41–50 years at baseline than among women in the same age group (Figure). The population attributable fraction of CB due to different risk factors at follow-up was 22.4% for current smoking and 25.1% for ever asthma.
DISCUSSION This prospective general population-based study from a county in western Sweden reports an incidence rate of 0.9/1000 py for CB, and a cumulative incidence of approximately 0.9% during the study period (1993–2003). Smoking increased the risk of CB incidence in women, but it did not seem to significantly increase the risk in men. In addition, asthma was associated with incident CB. The present study has several strengths. The most apparent is the prospective design, which reduces recall bias. The response rate was relatively high among the large number of subjects who were randomly selected from a general adult population and invited to participate in the study, increasing the
Table 3 Risk of chronic bronchitis by smoking exposure in relation to sex, atopy, age and asthma in four Cox regression models Smoking years Ex-smoking years Never-smoking years HR (95%CI) HR (95%CI) HR (95%CI) Current smoking at baseline* Female sex* Atopic at baseline* Age at baseline† Asthma 1993 or 2003*
1.9 1.1 1.3 5.7
NA (0.9–3.9) (0.5–2.4) (0.9–1.9) (2.8–11.5)
0.8 1.1 0.8 7.8
NA (0.3–1.9) (0.4–2.7) (0.5–1.4) (3.1–19.5)
* 1 ¼ yes and 0 ¼ no. † 1 ¼ 20–30 years; 2 ¼ 31–40 years; 3 ¼ 41–50 years. HR ¼ hazard ratio; CI ¼ confidence interval; NA ¼ not applicable.
0.8 1.0 1.3 3.6
NA (0.4–1.5) (0.4–2.4) (0.9–2.0) (1.4–9.3)
All HR (95%CI) 2.1 1.1 1.1 1.2 5.6
(1.4–3.2) (0.7–1.7) (0.7–1.7) (0.9–1.5) (3.5–9.0)
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Figure Smoking status, atopy and asthma at baseline in different age groups among A) women and B) men.
likelihood that the study population is representative of the entire target population. We did not perform any analysis of non-responders, although this is suggested by Bakke as a means of avoiding selection bias.27 In a recent study, no difference regarding respiratory symptoms and airway diseases was found between responders and non-responders,28 but other studies have reported less29 and more30 respiratory symptoms among non-responders. To define CB, we did not use physician-diagnosed CB but self-reported symptoms, which may have led to an overestimation of CB incidence. However, the diagnostic criterion16,17 is based solely on symptoms, which implies that self-reported symptoms from a questionnaire can be used to detect CB. Moreover, asking for physiciandiagnosed CB is complicated, as in Sweden the term ‘chronic bronchitis’ has historically been used to describe both COPD and symptoms of CB. Another limitation of this questionnaire-based study is that the participants did not undergo spirometry testing or testing for atopy. In addition, individuals who did not report any year of onset or year of onset before baseline were excluded, which affected the CB incidence rate. However, we needed a correct year of onset during follow-up to perform the analyses of explanatory variables. Despite the study limitations, there are good reasons to believe that the results of the study could be valid for other, similar populations. Only a few studies have investigated CB incidence in general populations,14,21-24 and CB incidence rates are presented only in one.24 Two of the cited incidence studies included only men,14,21 and one only included members of ‘White, non-MexicanAmerican households’.22
Another problem is that the definition of CB varies between studies. Pelkonen et al. included not only CB diagnosed from questionnaire-based self-reported symptoms in their analyses but also deaths due to CB.14 They followed men, mostly farmers, from two rural cohorts for 30 years, and found that the cumulative incidence of CB was 42% in continuous smokers, 26% in ex-smokers and 22% in never smokers.14 The relatively high cumulative incidence of CB was suggested to be partly due to high exposure to airborne agents in farming.14 Pelkonen et al.’s study population was older than ours, and their definition of CB was not wholly identical to the one we used. In a 10-year follow-up of 9023 individuals (aged 30–64 years at follow-up), Ellison-Loschmann et al. defined CB as presence of both cough and phlegm on most days for at least 3 months during the previous year. They found a cumulative incidence of 1.3%, which is close to our findings.23 In another study, 3099 adult subjects from Tucson, AZ, USA, were followed over a period of 20 years and nearly 3% developed CB.22 This cumulative incidence is similar to the one we found; however, the authors based the CB diagnosis both on the internationally accepted diagnostic criterion, i.e., chronic productive cough at least 3 months per year for 2 consecutive years,16,17 and FEV1 value ,80% of predicted FEV1, which most certainly lowered the incidence of reported CB. Dontas et al. performed a relatively small study of men, mostly farmers, on the island of Crete. In their study, CB was diagnosed clinically, using criteria from the British Medical Research Council.21 They found that approximately 6% of never smokers had developed CB after 5 or 10 years,
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and further showed that smoking enhanced development of CB in a dose-response pattern. Their study population was older than ours. A Korean 4-year follow-up study using the same diagnostic criterion for CB as ours, found an incidence rate of 27.1 cases/ 1000 py for CB.24 This is 30 times higher than ours, and we do not have any explanation for this large discrepancy, except that their study population was older. These incidence studies were performed in populations older than ours,14,21,22,24 except for one with roughly the same age range.23 A strong association between smoking and incident CB was shown in our study, but only in women. In a large systematic review with meta-analysis, adjusted RR estimates for CB were elevated for current smoking (RR 3.4) and ex-smoking (RR 1.6); RRs tended to be higher for men.3 However, the metaanalysis on CB was based to a large extent on prevalence studies, and CB incidence was covered in only three of the 87 principal studies included in the review. Over 10 years of follow-up (1980–1990), a large prospective questionnaire-based cohort study of US nurses found a significantly higher risk of CB in smokers than in never smokers, and also identified the presence of a dose-response relationship.31 The authors also reported that women who quit smoking gradually approached the risk of never smokers.31 These data are in agreement with our own results. The lack of association between smoking and incident CB in men in our study is interesting but difficult to explain. It has been shown that older smokers tend to under-report symptoms indicative of CB and this may, in part, explain the results, as the male smokers in our study in general were older than female smokers.32 The result could also be attributed to a cohort effect, where men who have chosen to continue smoking are healthier and do not appear to suffer from the adverse effects of smoking, so-called ‘healthy smokers’.33,34 This is supported by the fact that there tended to be more ex-smokers among older men than among older women in our study. Our finding of an increased risk of ever having had CB in men self-reporting as smokers at baseline suggests that the attributes of the male smoking population have changed over time. In addition, some studies have indicated that men, and particularly healthy male smokers, have a diminished cough reflex sensitivity.35-38 In those reporting asthma at baseline, very few developed CB, and among never smokers no-one did so. However, among the new CB cases approximately 30% reported physician-diagnosed asthma, and among the new CB cases with atopy at baseline, 50% reported the same diagnosis. This is interesting as it has been difficult to separate the two diagnoses, and asthma patients are overrepresented among those with CB.8 Symptoms of asthma could undoubtedly be the same as in patients with CB, but a variable airway
obstruction should also be present. Atopy has been associated with CB in previous studies.39,40 The present study confirms this finding, but shows that it is mediated by new-onset asthma. CB prevalence seems to increase with age;2 however, according to data from Pelkonen et al., CB incidence appears to be relatively constant in middle age and then level off. 14 In our middle-aged population there was a tendency, although not significant, for an age-dependent increase in CB incidence rate.
CONCLUSIONS This prospective study reports CB incidence rates in a general population. It shows that smoking is significantly associated with an increased CB incidence in women, and that asthma seems to be related to an increased risk of CB. Acknowledgements This study received financial support from the Swedish Heart and Lung Foundation and the Swedish Council for Working Life and Social Research. Conflict of interest: none declared.
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RESUME
Un cont´e de l’Ouest de la Su`ede. Rechercher prospectivement le taux d’incidence de la bronchite chronique (CB) en relation avec le fait de fumer, l’age, ˆ le sexe, l’atopie et l’asthme dans un e´ chantillon de population g´en´erale de grande taille. S C H E´ M A : Les sujets d’un cont´e de l’Ouest de la Su`ede n´es entre 1943 et 1973, qui avaient particip´e a` notre e´ tude pre´ c e´ dente en 1993, ont re c¸ u un nouveau questionnaire en 2003. Au total, 11 463 (72%) ont r´epondu au questionnaire, qui comportait des questions relatives au fait de fumer, a` l’atopie, aux symptomes ˆ ˆ d’apparition des symptomes ˆ respiratoires et a` l’age de CB. La CB e´ tait d´efinie comme une toux productive chronique durant au moins 3 mois par an pendant 2 ann´ees cons´ecutives. CONTEXTE : OBJECTIF :
De 1993 a` 2003, 98 nouveaux cas de CB ont e´ t´e identifies dans la population d’´etude ag´ ˆ ee de 30 a` 60 ans lors du suivi. Le taux d’incidence e´ tait de 0,9/ 1000 personnes-ann´ees (py), sans diff´erence significative entre les hommes et les femmes ou en fonction de l’age. ˆ Cependant, l’incidence de la CB e´ tait plus e´ lev´ee chez les femmes qui fumaient (ratio d’incidence 3,6 ; IC95% 1,9–7,3) et chez ceux qui avaient pr´esent´e un asthme (risque r´elatif 5,6 ; IC95% 3,5–9,0). C O N C L U S I O N : Cette e´ tude prospective en population g´en´erale montre une incidence de CB de 0,9/1000 py. Le fait de fumer et l’asthme sont tous deux associ´es a` un risque plus e´ lev´e de CB. R E´ S U LT A T S :
RESUMEN M A R C O D E R E F E R E N C I A:
Un condado en el occidente
de Suecia. Investigar de manera prospectiva la incidencia de bronquitis cronica ´ (CB) en funcion ´ del tabaquismo, la edad, el sexo, la atopia y el asma en una muestra grande de la poblacion ´ general. M E´ T O D O: En el 2003, se envio ´ por correo un nuevo cuestionario a los pacientes nacidos entre 1943 y 1973 que hab´ıan participado en un estudio previo en 1993 en un condado al occidente de Suecia. Respondieron el cuestionario 11 463 personas (72%). El cuestionario abarcaba aspectos del tabaquismo, la atopia, los s´ıntomas respiratorios y la edad, al comienzo de los s´ıntomas de CB. Se definio´ la CB como la presencia de tos productiva durante por lo menos 3 meses por ano, ˜ en 2 anos consecutivos. ˜ O B J E T I V O:
Se detectaron 98 casos nuevos de CB entre 1993 y el 2003 en la poblacion ´ del estudio, con una edad entre 30 anos y 60 anos en el momento del ˜ ˜ seguimiento. La tasa de incidencia fue 0,9 por 1000 anos-persona (py); no se observaron diferencias ˜ significativas entre hombres y mujeres o en diferentes grupos de edad. Sin embargo, la incidencia de CB aumento´ en las mujeres en funcion ´ del tabaquismo (razon ´ de tasas de incidencia 3,6; IC95% 1,9–7,3) y el diagnostico ´ de asma en algun ´ momento (cociente de riesgos instanta´neos 5,6; IC95% 3,5–9,0). ´ N: El presente estudio prospectivo en la CONCLUSIO poblacion ´ general pone de manifiesto una tasa de incidencia de CB de 0,9 por 1000 py. El tabaquismo y el asma se asocian con un mayor riesgo de padecer CB. R E S U LT A D O S:
Incidence of chronic bronchitis: a prospective study in a large general population † E. Andersson* ´ M. Holm,* K. Toren,*
*Department of Occupational and Environmental Medicine, Sahlgrenska University Hospital, Goteborg, ¨ Sweden; † Section of Occupational Medicine, Respiratory Diseases and Toxicology, University of Perugia, Perugia, Italy SUMMARY
A county in western Sweden. To prospectively investigate the incidence rate of chronic bronchitis (CB) in relation to smoking, age, sex, atopy and asthma in a large sample of the general population. D E S I G N : Subjects from a county in western Sweden born between 1943 and 1973, who had participated in our previous study in 1993, were mailed a new questionnaire in 2003. Altogether 11 463 (72%) answered the questionnaire, which comprised items about smoking, atopy, respiratory symptoms and age at onset of CB symptoms. CB was defined as chronic productive cough for at least 3 months per year for 2 consecutive years.
There were 98 new cases of CB during 1993– 2003 in the study population aged 30-60 years at followup. The incidence rate was 0.9/1000 person-years (py); there was no significant difference between women and men or different age groups. However, CB incidence was higher in women in relation to smoking (incidence rate ratio 3.6, 95%CI 1.9–7.3) and in those with ever asthma (hazard ratio 5.6, 95%CI 3.5–9.0). C O N C L U S I O N : This prospective general populationbased study shows an incidence rate of CB of 0.9/1000 py. Smoking and asthma were both associated with an increased risk of CB. K E Y W O R D S : chronic bronchitis; epidemiology; prospective; general population
AS REPORTED in a systematic review with metaanalysis, chronic bronchitis (CB) is a common disease with a calculated pooled global prevalence of 6.4%.1 CB prevalence is higher in middle-aged and elderly individuals, which, it has been suggested, may reflect a cohort effect rather than an effect of ageing.2 Another recent systematic review confirms that there is a close relation between CB and smoking.3 In addition, an association between CB and workrelated exposures to gas, dust and fumes,4-6 and, more specifically, welding fumes,7,8 has been shown. Finally, self-reported frequent chest infections in childhood have also been shown to presage CB.9 Historically, there have been several definitions of CB, and the condition has been closely associated with chronic obstructive pulmonary disease (COPD). Some studies have reported that the presence of chronic mucus production from the airways is not associated with the decline in forced expiratory volume in 1 second (FEV1) seen in COPD,10,11 while other studies have reported the opposite.12-14 It has been suggested that CB does not increase the risk of initial excess decline in FEV1 but exacerbates the process once it has started.2,15 Today, CB is usually
defined by the internationally accepted diagnostic criterion of a chronic productive cough for at least 3 months per year for 2 consecutive years,16,17 and it has been recommended that the term CB should be used only to indicate bronchial hypersecretion and never to denote associated airflow obstruction.18 It is important to study CB, as some studies have reported increased overall mortality even in subjects without reduced lung function.9,14,19,20 CB prevalence has been investigated by several groups, but few prospective studies have examined CB incidence in general populations.14,21-24 In addition, the definition of CB varies between these incidence studies; only Baik et al. have presented incidence rates for CB.24 The aim of the present prospective study was to investigate the incidence rate of CB in relation to smoking, age, sex, atopy and asthma in a large sample of the general population.
SETTING:
OBJECTIVE:
R E S U LT S :
STUDY POPULATION AND METHODS A random sample of 20 000 individuals in a county in western Sweden, born between 1943 and 1973, were sent a questionnaire in 1993. The questionnaire,
Correspondence to: Mathias Holm, Department of Occupational and Environmental Medicine, Box 414, SE 405 30 Goteborg, Sweden. Tel: (þ46) 317 866 279. Fax: (þ46) 3140 9728. e-mail: [email protected] ¨ Article submitted 4 September 2013. Final version accepted 15 March 2014.
Incidence of chronic bronchitis
which comprised items about airway symptoms and smoking, was answered by 15 813 subjects.25 At follow-up in 2003, the subjects were mailed a new questionnaire and 11 463 (72%) answered the questionnaire. However, 52 could not be linked to the first questionnaire and 4 had unreasonable smoking cessation data, leaving 11 407. The followup questionnaire contained new questions as well as questions identical to those in the baseline questionnaire. The internationally accepted diagnostic criterion, chronic productive cough for at least 3 months per year for 2 consecutive years, was used to define CB.16,17 CB was diagnosed in individuals who answered positively to all three of the following questions, which were included in both the baseline questionnaire and the follow-up questionnaire: ‘Have you, since the age of 15, suffered from long-standing cough with sputum?’, ‘If yes, has any period lasted for at least 3 months?’ and ‘If yes, have you had such periods for at least 2 consecutive years?’ In addition, the 2003 questionnaire also asked, ‘If yes, how old were you when these problems started?’ Atopy was defined as a positive answer to the question ‘Do you have, or have you ever had, hay fever?’ and/or ‘Do you have, or have you had, atopic dermatitis?’ Asthma was defined as an affirmative answer to the question ‘Have you been diagnosed as having asthma by a physician?’26 Smoking status was checked both at baseline and at follow-up, and was categorised as ‘never smoking’, ‘ex-smoking’ and ‘current smoking’. Year of starting to smoke and year of quitting smoking were also asked for, allowing us to classify every year into one of the smoking categories and thus calculate person-years (py). The SAS statistical package, version 9.2 (Statistical Analysis Software Institute, Cary, NC, USA), was used for most of the analyses. STATA (Stata Corp, College Station, TX, USA) was used for the incidence analyses. The incidence rate of CB (number of new cases/1000 py) with 95% confidence intervals (CIs) was calculated for the period 1993–2003. This was based on reported year of onset (‘How old were you when these symptoms started?’), with 2 years added to fulfil the diagnostic criterion.16,17 Subjects who met the diagnostic criterion for CB at baseline (n ¼ 168), or who reported year of onset before 1991 at Table 1
follow-up (n ¼ 73) or reported no year of onset (n ¼ 18) were excluded from the analyses. Subjects ceased to contribute py when they were diagnosed with CB. The py were divided into smoking, ex-smoking and non-smoking years. Incidence rate ratios with 95%CIs were calculated, comparing smoking py with non-smoking py. Cox regression analyses (PROC PHREG; Statistical Analysis Software Institute) were performed, with incident CB as an event and py under observation as the dependent variable. Hazard ratios (HRs) were calculated for the explanatory variables sex, atopy, asthma and age group (20– 30, 31–40 and 41–50 years) included simultaneously in the model for smoking, ex-smoking and nonsmoking years, respectively. When applying a model with all subjects, current smoking was included. The population attributable fraction of CB due to different risk factors was calculated using the formula: [(RR1)/RR*(exposed cases/cases)] (RR ¼ relative risk). The study was approved by the Ethics Committee ¨ 192-03). of Goteberg, Sweden (O ¨
RESULTS Among those who answered both questionnaires, CB prevalence was 1.5% in 1993 and 2.1% in 2003. After exclusion of individuals with CB at baseline and of those with no reported year of onset, 11 148 remained, representing a total of 109 410 py. The demographic characteristics for these subjects are shown in Table 1. There were 98 new CB cases during 1993–2003; the cumulative incidence for CB was 0.9% in the study population aged 30–60 years at follow-up. Around 30% of new CB cases also reported newonset (1993–2003) physician-diagnosed asthma. The crude incidence rate was 0.9/1000 py (95%CI 0.7– 1.1: 1.0/1000 py, 95%CI 0.7–1.3 in women and 0.8/ 1000 py, 95%CI 0.6-1.1 in men). Those individuals reporting atopy at baseline had an incidence rate of 1.2/1000 py (95%CI 0.8–1.7). There were only three new CB cases among those reporting asthma at baseline. Smokers had an incidence rate of 1.5/1000 py (95%CI 1.0–2.0). Table 2 shows incidence rates and RRs of CB by sex, atopy, age and asthma in the
Demographic characteristics of the study population at baseline by smoking groups
All Female subjects Subjects with atopy Subjects with asthma Age, years, mean 6 SD
Smokers n (%)
Ex-smokers n (%)
Never smokers n (%)
All* n (%)
3100 (27.8)† 1811 (58.4) 513 (16.6) 115 (3.7) 37.0 6 8.7
2238 (20.1)† 1127 (50.4) 480 (21.5) 102 (4.6) 39.7 6 7.5
5342 (47.9)† 2748 (51.4 ) 1261 (23.6) 199 (3.7) 34.3 6 9.1
11 148 (100)† 5918 (53.1) 2350 (21.1) 438 (3.9) 36.1 6 8.9
* Includes also those with missing smoking data. † Percentage of all individuals in the study. SD ¼ standard deviation.
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Table 2 Incidence rates (cases/1000 py) and relative risk of chronic bronchitis in relation to sex, atopy, age and asthma by smoking exposure Smoking years Incidence rate (95%CI) All Women Men Atopic* Non-atopic* 20–30 years* 31–40 years* 41–50 years* Asthma* Asthma 1993 or 2003
1.5 1.8 0.9 2.3 1.3 1.1 1.6 1.6 1.8 5.7
(1.0–2.0) (1.3–2.6) (0.4–1.6) (1.1–4.0) (0.9–1.8) (0.5–2.0) (0.9–2.7) (0.9–2.5) (0.2–6.3) (3.1–9.6)
Ex-smoking years Incidence rate (95%CI) 0.9 0.8 0.9 1.2 0.7 1.5 0.9 0.6 0.8 3.9
Never-smoking years Incidence rate (95%CI)
(0.6–1.3) (0.4–1.5) (0.5–1.6) (0.5–2.5) (0.4–1.2) (0.6–3.0) (0.4–1.7) (0.3–1.2) (0.02–4.7) (1.8–7.5)
Incidence rate ratio (smoking/never smoking years) Incidence rate (95%CI)
0.6 0.5 0.7 0.7 0.6 0.5 0.7 0.7
(0.4–0.9) (0.3–0.9) (0.4–1.1) (0.3–1.4) (0.4–0.9) (0.2–0.9) (0.4–1.3) (0.3–1.2) NA 1.9 (0.8–3.9)
2.4 3.6 1.2 3.1 2.3 2.3 2.3 2.3
(1.5–3.9) (1.9–7.3) (0.5–2.8) (1.2–8.6) (1.3–4.2) (0.8–6.3) (0.99–5.5) (1.03–5.4) NA 3.0 (1.1–8.9)
* At baseline. py ¼ person-years; RR ¼ relative risk; CI ¼ confidence interval; NA ¼ not applicable.
different smoking groups. Smoking seems to have increased the risk for incident CB in all groups but men (Table 2). If those who met the diagnostic criterion for CB in 2003 (but not in 1993) and reported no year of onset (n ¼ 18) or year of onset before 1993 (n ¼ 73) were included, the crude incidence rate was 1.7/1000 py (1998 was used as year of onset in this calculation, as it represented the midpoint in the 1993–2003 follow-up period). The relative importance of the studied variables associated with CB incidence did not substantially change when these individuals were included in the analyses. The Cox regression model, with mutual adjustments for all predictors, showed an increased RR for CB among current smokers and among subjects with asthma compared with those without asthma (Table 3). Among atopic subjects with incident CB, around 50% also had physician-diagnosed asthma (not shown). If ‘asthma 1993 or 2003’ was excluded from the analysis, atopy at baseline was associated with an increased risk of CB (HR 1.6, 95%CI 1.0–2.5). There was no significant difference between women and men, and the same was true when different age groups were compared (Table 3). The results concerning sex, atopy, age and asthma remained similar when a model including different smoking groups was used, except that female smokers seemed to have a non-significantly increased risk of incident CB compared with male smokers (Table 3). However,
men who were smokers at baseline were found to report ever having had symptoms of CB (in the 1993 and/or 2003 questionnaire) more often than men who were never-smokers (odds ratio [OR] 1.4, 95%CI 1.0–2.1). Male smokers were in general older than female smokers (mean age 37.9 vs. 36.4 years, P , 0.0001), and there tended to be more ex-smokers among men aged 41–50 years at baseline than among women in the same age group (Figure). The population attributable fraction of CB due to different risk factors at follow-up was 22.4% for current smoking and 25.1% for ever asthma.
DISCUSSION This prospective general population-based study from a county in western Sweden reports an incidence rate of 0.9/1000 py for CB, and a cumulative incidence of approximately 0.9% during the study period (1993–2003). Smoking increased the risk of CB incidence in women, but it did not seem to significantly increase the risk in men. In addition, asthma was associated with incident CB. The present study has several strengths. The most apparent is the prospective design, which reduces recall bias. The response rate was relatively high among the large number of subjects who were randomly selected from a general adult population and invited to participate in the study, increasing the
Table 3 Risk of chronic bronchitis by smoking exposure in relation to sex, atopy, age and asthma in four Cox regression models Smoking years Ex-smoking years Never-smoking years HR (95%CI) HR (95%CI) HR (95%CI) Current smoking at baseline* Female sex* Atopic at baseline* Age at baseline† Asthma 1993 or 2003*
1.9 1.1 1.3 5.7
NA (0.9–3.9) (0.5–2.4) (0.9–1.9) (2.8–11.5)
0.8 1.1 0.8 7.8
NA (0.3–1.9) (0.4–2.7) (0.5–1.4) (3.1–19.5)
* 1 ¼ yes and 0 ¼ no. † 1 ¼ 20–30 years; 2 ¼ 31–40 years; 3 ¼ 41–50 years. HR ¼ hazard ratio; CI ¼ confidence interval; NA ¼ not applicable.
0.8 1.0 1.3 3.6
NA (0.4–1.5) (0.4–2.4) (0.9–2.0) (1.4–9.3)
All HR (95%CI) 2.1 1.1 1.1 1.2 5.6
(1.4–3.2) (0.7–1.7) (0.7–1.7) (0.9–1.5) (3.5–9.0)
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Figure Smoking status, atopy and asthma at baseline in different age groups among A) women and B) men.
likelihood that the study population is representative of the entire target population. We did not perform any analysis of non-responders, although this is suggested by Bakke as a means of avoiding selection bias.27 In a recent study, no difference regarding respiratory symptoms and airway diseases was found between responders and non-responders,28 but other studies have reported less29 and more30 respiratory symptoms among non-responders. To define CB, we did not use physician-diagnosed CB but self-reported symptoms, which may have led to an overestimation of CB incidence. However, the diagnostic criterion16,17 is based solely on symptoms, which implies that self-reported symptoms from a questionnaire can be used to detect CB. Moreover, asking for physiciandiagnosed CB is complicated, as in Sweden the term ‘chronic bronchitis’ has historically been used to describe both COPD and symptoms of CB. Another limitation of this questionnaire-based study is that the participants did not undergo spirometry testing or testing for atopy. In addition, individuals who did not report any year of onset or year of onset before baseline were excluded, which affected the CB incidence rate. However, we needed a correct year of onset during follow-up to perform the analyses of explanatory variables. Despite the study limitations, there are good reasons to believe that the results of the study could be valid for other, similar populations. Only a few studies have investigated CB incidence in general populations,14,21-24 and CB incidence rates are presented only in one.24 Two of the cited incidence studies included only men,14,21 and one only included members of ‘White, non-MexicanAmerican households’.22
Another problem is that the definition of CB varies between studies. Pelkonen et al. included not only CB diagnosed from questionnaire-based self-reported symptoms in their analyses but also deaths due to CB.14 They followed men, mostly farmers, from two rural cohorts for 30 years, and found that the cumulative incidence of CB was 42% in continuous smokers, 26% in ex-smokers and 22% in never smokers.14 The relatively high cumulative incidence of CB was suggested to be partly due to high exposure to airborne agents in farming.14 Pelkonen et al.’s study population was older than ours, and their definition of CB was not wholly identical to the one we used. In a 10-year follow-up of 9023 individuals (aged 30–64 years at follow-up), Ellison-Loschmann et al. defined CB as presence of both cough and phlegm on most days for at least 3 months during the previous year. They found a cumulative incidence of 1.3%, which is close to our findings.23 In another study, 3099 adult subjects from Tucson, AZ, USA, were followed over a period of 20 years and nearly 3% developed CB.22 This cumulative incidence is similar to the one we found; however, the authors based the CB diagnosis both on the internationally accepted diagnostic criterion, i.e., chronic productive cough at least 3 months per year for 2 consecutive years,16,17 and FEV1 value ,80% of predicted FEV1, which most certainly lowered the incidence of reported CB. Dontas et al. performed a relatively small study of men, mostly farmers, on the island of Crete. In their study, CB was diagnosed clinically, using criteria from the British Medical Research Council.21 They found that approximately 6% of never smokers had developed CB after 5 or 10 years,
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and further showed that smoking enhanced development of CB in a dose-response pattern. Their study population was older than ours. A Korean 4-year follow-up study using the same diagnostic criterion for CB as ours, found an incidence rate of 27.1 cases/ 1000 py for CB.24 This is 30 times higher than ours, and we do not have any explanation for this large discrepancy, except that their study population was older. These incidence studies were performed in populations older than ours,14,21,22,24 except for one with roughly the same age range.23 A strong association between smoking and incident CB was shown in our study, but only in women. In a large systematic review with meta-analysis, adjusted RR estimates for CB were elevated for current smoking (RR 3.4) and ex-smoking (RR 1.6); RRs tended to be higher for men.3 However, the metaanalysis on CB was based to a large extent on prevalence studies, and CB incidence was covered in only three of the 87 principal studies included in the review. Over 10 years of follow-up (1980–1990), a large prospective questionnaire-based cohort study of US nurses found a significantly higher risk of CB in smokers than in never smokers, and also identified the presence of a dose-response relationship.31 The authors also reported that women who quit smoking gradually approached the risk of never smokers.31 These data are in agreement with our own results. The lack of association between smoking and incident CB in men in our study is interesting but difficult to explain. It has been shown that older smokers tend to under-report symptoms indicative of CB and this may, in part, explain the results, as the male smokers in our study in general were older than female smokers.32 The result could also be attributed to a cohort effect, where men who have chosen to continue smoking are healthier and do not appear to suffer from the adverse effects of smoking, so-called ‘healthy smokers’.33,34 This is supported by the fact that there tended to be more ex-smokers among older men than among older women in our study. Our finding of an increased risk of ever having had CB in men self-reporting as smokers at baseline suggests that the attributes of the male smoking population have changed over time. In addition, some studies have indicated that men, and particularly healthy male smokers, have a diminished cough reflex sensitivity.35-38 In those reporting asthma at baseline, very few developed CB, and among never smokers no-one did so. However, among the new CB cases approximately 30% reported physician-diagnosed asthma, and among the new CB cases with atopy at baseline, 50% reported the same diagnosis. This is interesting as it has been difficult to separate the two diagnoses, and asthma patients are overrepresented among those with CB.8 Symptoms of asthma could undoubtedly be the same as in patients with CB, but a variable airway
obstruction should also be present. Atopy has been associated with CB in previous studies.39,40 The present study confirms this finding, but shows that it is mediated by new-onset asthma. CB prevalence seems to increase with age;2 however, according to data from Pelkonen et al., CB incidence appears to be relatively constant in middle age and then level off. 14 In our middle-aged population there was a tendency, although not significant, for an age-dependent increase in CB incidence rate.
CONCLUSIONS This prospective study reports CB incidence rates in a general population. It shows that smoking is significantly associated with an increased CB incidence in women, and that asthma seems to be related to an increased risk of CB. Acknowledgements This study received financial support from the Swedish Heart and Lung Foundation and the Swedish Council for Working Life and Social Research. Conflict of interest: none declared.
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i
RESUME
Un cont´e de l’Ouest de la Su`ede. Rechercher prospectivement le taux d’incidence de la bronchite chronique (CB) en relation avec le fait de fumer, l’age, ˆ le sexe, l’atopie et l’asthme dans un e´ chantillon de population g´en´erale de grande taille. S C H E´ M A : Les sujets d’un cont´e de l’Ouest de la Su`ede n´es entre 1943 et 1973, qui avaient particip´e a` notre e´ tude pre´ c e´ dente en 1993, ont re c¸ u un nouveau questionnaire en 2003. Au total, 11 463 (72%) ont r´epondu au questionnaire, qui comportait des questions relatives au fait de fumer, a` l’atopie, aux symptomes ˆ ˆ d’apparition des symptomes ˆ respiratoires et a` l’age de CB. La CB e´ tait d´efinie comme une toux productive chronique durant au moins 3 mois par an pendant 2 ann´ees cons´ecutives. CONTEXTE : OBJECTIF :
De 1993 a` 2003, 98 nouveaux cas de CB ont e´ t´e identifies dans la population d’´etude ag´ ˆ ee de 30 a` 60 ans lors du suivi. Le taux d’incidence e´ tait de 0,9/ 1000 personnes-ann´ees (py), sans diff´erence significative entre les hommes et les femmes ou en fonction de l’age. ˆ Cependant, l’incidence de la CB e´ tait plus e´ lev´ee chez les femmes qui fumaient (ratio d’incidence 3,6 ; IC95% 1,9–7,3) et chez ceux qui avaient pr´esent´e un asthme (risque r´elatif 5,6 ; IC95% 3,5–9,0). C O N C L U S I O N : Cette e´ tude prospective en population g´en´erale montre une incidence de CB de 0,9/1000 py. Le fait de fumer et l’asthme sont tous deux associ´es a` un risque plus e´ lev´e de CB. R E´ S U LT A T S :
RESUMEN M A R C O D E R E F E R E N C I A:
Un condado en el occidente
de Suecia. Investigar de manera prospectiva la incidencia de bronquitis cronica ´ (CB) en funcion ´ del tabaquismo, la edad, el sexo, la atopia y el asma en una muestra grande de la poblacion ´ general. M E´ T O D O: En el 2003, se envio ´ por correo un nuevo cuestionario a los pacientes nacidos entre 1943 y 1973 que hab´ıan participado en un estudio previo en 1993 en un condado al occidente de Suecia. Respondieron el cuestionario 11 463 personas (72%). El cuestionario abarcaba aspectos del tabaquismo, la atopia, los s´ıntomas respiratorios y la edad, al comienzo de los s´ıntomas de CB. Se definio´ la CB como la presencia de tos productiva durante por lo menos 3 meses por ano, ˜ en 2 anos consecutivos. ˜ O B J E T I V O:
Se detectaron 98 casos nuevos de CB entre 1993 y el 2003 en la poblacion ´ del estudio, con una edad entre 30 anos y 60 anos en el momento del ˜ ˜ seguimiento. La tasa de incidencia fue 0,9 por 1000 anos-persona (py); no se observaron diferencias ˜ significativas entre hombres y mujeres o en diferentes grupos de edad. Sin embargo, la incidencia de CB aumento´ en las mujeres en funcion ´ del tabaquismo (razon ´ de tasas de incidencia 3,6; IC95% 1,9–7,3) y el diagnostico ´ de asma en algun ´ momento (cociente de riesgos instanta´neos 5,6; IC95% 3,5–9,0). ´ N: El presente estudio prospectivo en la CONCLUSIO poblacion ´ general pone de manifiesto una tasa de incidencia de CB de 0,9 por 1000 py. El tabaquismo y el asma se asocian con un mayor riesgo de padecer CB. R E S U LT A D O S:
